Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient

ABSTRACT

A compound represented by formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein the symbols in the formula are the same meanings as those in specification, salts thereof, solvates thereof, or prodrugs thereof binds to DP receptor and shows antagonistic activity for DP receptor. Thus, it is useful for prevention and/or treatment of diseases such as allergic disease (e.g., allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food allergy), systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, urticaria, eczema, diseases accompanied by itch (e.g., atopic dermatitis and urticaria), diseases (e.g., cataract, retinal detachment, inflammation, infection and sleeping disorders) which is generated secondarily as a result of behavior accompanied by itch (e.g., scratching and beating), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, chronic rheumatoid arthritis, pleurisy, ulcerative colitis, etc. Since it specifically binds to DP receptor and binds weakly to other prostaglandins receptors, they can be pharmaceuticals having little side effect.

TECHNICAL FIELD

The present invention relates to (1) a carboxylic acid compoundrepresented by formula (I)

wherein all symbols have the same meanings as follows, salts thereof,solvates thereof, and prodrugs thereof,

-   (2) a process for producing the same,-   (3) a pharmaceutical composition containing the same as an active    ingredient, and-   (4) a usage for the same.

BACKGROUND OF THE INVENTION

Prostaglandin D₂ (abbreviated as PGD₂) has been known as one ofmetabolites produced via an arachidonic acid cascade and is consideredto be one of chemical mediators participating in allergic diseases suchas allergic rhinitis, bronchial asthma and allergic conjunctivitis. Ithas been known that PGD₂ is mainly produced in and released from mastcells and that the PGD₂ released shows contraction of bronchus,promotion of vascular permeability, dilation or contraction of bloodvessels, promotion of mucus secretion and inhibition of plateletaggregation. It has been also reported that PGD2 inducesbronchoconstriction and nasal obstruction in vivo as well and increasedamounts of production of PGD₂ in pathological lesion of patientssuffering from systemic mastocytosis, allergic rhinitis, bronchialasthma, atopic dermatitis, urticaria, etc. (N. Engl. J. Med. 1989; 303:1400-4, Am. Rev. Respir. Dis. 1983; 128: 597-602, J. Allergy Clin.Immunol. 1991; 88: 33-42, Arch. Otolaryngol. Head Neck Surg. 1987; 113:179-83, J. Allergy Clin. Immunol. 1988; 82: 869-77, J. Immunol. 1991;146: 671-6, J. Allergy Clin. Immunol. 1989; 83: 905-12, N. Eng. J. Med.1986; 315: 8004, Am. Rev. Respir. Dis. 1990; 142, 126-32, J. AllergyClin. Immunol. 1991; 87: 540-8, J. Allergy Clin. Immunol 1986; 78:458-61). PGD₂ has been also reported to participate in nerve activity,particularly in sleeping, hormone secretion and pain. Furthermore, ithas been also reported that it participates in platelet aggregation,glycogen metabolism and adjustment of intraocular pressure.

PGD₂ exerts its biological activity via binding to a DP receptor, whichis one of PGD₂ receptors. Since DP receptor antagonists bind to itsreceptor and show antagonistic activity, DP receptor antagonists havebeen believed to be useful for prevention and/or treatment of diseasessuch as allergic diseases (e.g., allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma and food allergy),systemic mastocytosis, disorders accompanied by systemic mast cellactivation, anaphylactic shock, bronchoconstriction, urticaria, eczema,acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine,nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contactdermatitis, diseases accompanied by itch (e.g., atopic dermatitis,urticaria, allergic conjunctivitis, allergic rhinitis and contactdermatitis), diseases (e.g., cataract, retinal detachment, inflammation,infection and sleeping disorders) which are generated secondarily as aresult of behavior accompanied by itch (e.g., scratching and beating),inflammation, chronic obstructive pulmonary diseases, ischemicreperfusion injury, cerebrovascular accident, autoimmune disease,traumatic brain disorder, hepatopathy, graft rejection, chronicrheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease,ulcerative colitis, irritable bowel syndrome, interstitial cystitis,muscular dystrophy, polymyositis, multiple sclerosis, etc. It alsoparticipates in sleep and platelet aggregation and is believed to beuseful for those diseases as well.

For example, in the specification of WO86/05779, compounds representedby formula (T)

(in the formula, A^(T) is a hydrogen atom, phenyl or phenoxy; n^(T) isan integer from 3 to 10; R^(1T) is a hydrogen atom or a lower alkoxy;X^(1T) is —CH₂—Y^(1T)— (in the group, Y^(1T) is —O—, —S— or —NH—),—CO—Y^(2T)-(in the group, Y²T is —O—, —S— or —NH—) etc.;

is a group represented by the formula

etc.; R^(2T) is a hydrogen atom, a halogen atom, nitro, hydroxyl, loweralkoxy, cyano, lower alkyl, lower alkoxy lower alkyl, halo lower alkylor a group represented by —NR^(4T)R^(5T)T—, etc.; X^(2T) is a formula—Y^(3T)—Y^(4T)-(in the group, Y^(3T) is a single bond, —O—, —S— or —NH—and Y^(4T) is a C1-6 alkylene which may be interrupted by sulfur atom)etc.; and DT is carboxyl or a lower alkoxycarbonyl and the like) areuseful as antagonists for SRS-A (slow reacting substance ofanaphylaxis).

DISCLOSURE OF THE INVENTION

In prostaglandin receptors, there are many receptors including subtypesand each of them has a different pharmacological action. Now, if novelcompounds that specifically bind to DP receptors and bind weakly toother prostaglandin receptors can be found, they can be pharmaceuticalshaving little side effect since no other functions are not exerted.Therefore, such pharmaceuticals are requested to be found.

The inventors of the present invention have carried out intensivestudies for finding compounds that specifically bind to DP receptors andexert antagonistic activity, and as a result, they have found thatcarboxylic acid compounds represented by formula (I) resolve the problemto accomplish the present invention.

Thus, the present invention relates to the followings.

-   1. A carboxylic acid compound represented by formula (I)

wherein R¹ represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C2-4alkenyl, or (4) benzyl;

E represents —CO—, —SO₂—, or —CH₂—;

R² represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4)hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9)nitro, (10) —NR⁶R⁷, or (11) C1-4 alkyl substituted with —OR⁸, (12)oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15) —SR¹¹, or twoR²'s substituting for the adjacent carbon atom are taken together torepresent (1) C2-5 alkylene which may be substituted by a substituentwherein one carbon atom thereof may be replaced with an oxygen atom, anitrogen atom, or a sulfur atom which may be oxidized, or (2) C2-5alkenylene which may be substituted by a substituent, wherein one carbonatom thereof may be replaced with an oxygen atom, a nitrogen atom, or asulfur atom;

R³ represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4)hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9)nitro, (10) —NR⁶R⁷ or (11) C1-4 alkyl substituted with —OR⁸, (12)oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15) —SR¹¹;

R⁶ and R⁷ each independently represent a hydrogen atom or C1-4 alkyl;

R⁸ represents C1-4 alkyl, phenyl, or pyridyl;

R⁴ represents (1) a hydrogen atom, (2) C1-6 alkyl, (3) benzyl, or (4)oxidized C1-6 alkyl;

R⁵ represents (1) C1-6 alkyl, (2) C1-10 alkoxy, (3) C1-6 alkylsubstituted with C1-6 alkoxy, (4) a halogen atom, (5) hydroxyl, (6)trihalomethyl, (7) nitro, (8) —NR⁹R¹⁰, (9) phenyl, (10) phenoxy, (11)oxo, (12) C2-6 acyl, (13) cyano or (14) —SO₂R¹¹, (15) —SOR¹¹, (16)—SR¹¹, (12) oxidized C1-6 alkyl;

R⁹ and R¹⁰ each independently represent a hydrogen atom or C1-4 alkyl;and

R¹¹ represents C1-6 alkyl or phenyl which may be substituted;

wherein R⁶'s to R¹¹'s in R²'s to R⁵'s may be the same or eachindependently different:

represents a C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to12-membered monocyclic or bicyclic heterocycle;

G represents (1) C1-6 alkylene having 0 to 2 hetero atoms selected froma nitrogen atom, an oxygen atom, and a sulfur atom, (2) C2-6 alkenylenehaving 0 to 2 hetero atoms selected from a nitrogen atom, an oxygenatom, and a sulfur atom, or (3) C2-6 alkynylene having 0 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom;

represents a C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to12-membered monocyclic or bicyclic heterocycle;

m represents 0 or an integer of 1 to 4,

n represents 0 or an integer of 1 to 4, and

i represents 0 or an integer of 1 to 11,

wherein R²'s may be the same or different when m is 2 or more, R³'s maybe the same or different when n is 2 or more, and R⁵'s may be the sameor different when i is 2 or more; and

R¹² and R¹³ each independently represent (1) C1-4 alkyl which may beoxidized, (2) a halogen atom, (3) trihalomethyl, (4) hydroxyl which maybe protected, (5) amino which may be protected, (6) phenyl which may besubstituted, (7) pyridyl which may be substituted, or (8) a hydrogenatom, or R¹² and R¹³ are taken together to represent (1) oxo, (2) C2-5alkylene which may be substituted by a substituent, wherein one carbonatom thereof may be replaced with an oxygen atom, a nitrogen atom, or asulfur atom, or (3) C1-6 alkylidene which may be substituted, and

wherein when R¹² and R¹³ each simultaneously represent a hydrogen atom,the carboxylic acid compound represented by formula (I) represents acompound selected from the group consisting of the following compounds(1)-(32);

-   (1)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (2)    (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3)    (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4)    (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (5)    (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (6)    (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (7)    (4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (8)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (9)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (10)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (11)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (12)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (13)    (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (14)    (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (15)    (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (16)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (17)    (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (18)    (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (19)    (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (20)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (21)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (22)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (23)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (24)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (25)    (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (26)    (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (27)    (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (28)    (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (29)    (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (30)    (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-ly)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (31)    (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid, and-   (32)    (3-((4-(1,3-benzodioxol-2-lymethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic    acid, a salt thereof, a solvate thereof, or a prodrug thereof.-   2. The compound according to 1 above, wherein

wherein

represents C5-6 saturated carbocyclic ring, or 5- to 6-memberedsaturated heterocycle containing one or two nitrogen atoms, one or twooxygen atoms, and/or a sulfur atom;

represents C5-6 saturated carbocyclic ring, or 5- to 6-memberedsaturated heterocycle containing one or two nitrogen atoms, one or twooxygen atoms, and/or a sulfur atom;

represents a single bond or a double bond; and

the other symbols have the same meanings as defined in 1 above, a saltthereof, a solvate thereof, or a prodrug thereof.

-   3. The compound according to 2 above, wherein

is a group selected from dihydrobenzoxazin-2-yl, benzodioxan-2-yl,benzoxathiane-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl,benzodioxol-2-yl, indolin-2-yl, and indolin-3-yl.

-   4. The compound according to 2 above, wherein n is an integer of 2    to 4.-   5. The compound according to 4 above, wherein

wherein all symbols have the same meanings as defined in 1 above.

-   6. The compound according to 5 above, wherein

wherein all symbols have the same meanings as defined in 1 above.

-   7. The compound according to 6 above, wherein R³'s each    independently represent (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6    alkoxy, or (4) trihalomethyl.-   8. The compound according to 2 above, wherein R¹² and R¹³ each    independently represent (1) C1-4 alkyl, (2) a halogen atom, (3)    hydroxyl which may be protected, or (4) a hydrogen atom, or R¹² and    R¹³ are taken together to represent (1) oxo or (2) C2-5 alkylene    which may be substituted by a substituent, wherein one carbon atom    thereof may be replaced with an oxygen atom, a nitrogen atom, or a    sulfur atom.-   9. The compound according to 7 above, which is selected from:-   (1)    2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (2)    (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3)    (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)(oxo)acetic    acid,-   (4)    2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (5)    2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (6)    2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   (7)    1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (8)    1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (9)    1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (10)    (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)acetic    acid, and-   (11)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid.-   10. A pharmaceutical composition comprising a compound represented    by formula (I)

wherein all symbols have the same meanings as defined in 1 above, a saltthereof, a solvate thereof, or a prodrug thereof.

-   11. The pharmaceutical composition according to 10 above, which is    an antagonist of DP receptor.-   12. The pharmaceutical composition according to 10 above, which is    an agent for prevention and/or treatment of diseases mediated by DP    receptor.-   13. The pharmaceutical composition according to 12 above, wherein    the disease mediated by DP receptor is allergic disease, systemic    mastocytosis, disorders accompanied by systemic mast cell    activation, anaphylaxis shock, bronchoconstriction, urticaria,    eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis,    migraine, nasal polypus, anaphylactic vasculitis, eosinophilic    syndrome, contact dermatitis, diseases accompanied by itch, diseases    generated secondarily as a result of behavior accompanied by itch,    inflammation, chronic obstructive pulmonary diseases, ischemic    reperfusion injury, cerebrovascular accident, autoimmune disease,    traumatic brain disorder, hepatopathy, graft rejection, chronic    rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease,    ulcerative colitis, irritable bowel syndrome, interstitial cystitis,    muscular dystrophy, polymyositis, multiple sclerosis, sleeping    disorders or disease related to platelet aggregation.-   14. The pharmaceutical composition according to 13 above, wherein    the allergic disease is allergic rhinitis, allergic conjunctivitis,    atopic dermatitis, bronchial asthma or food allergy.-   15. A pharmaceutical composition comprising a combination of the    compound represented by formula (I) according to 1 above, a salt    thereof, a solvate thereof, or a prodrug thereof; and one or more    kinds selected from antihistaminic agent, suppressor for mediator    liberation, thromboxane synthetase inhibitor, antagonist for    thromboxane A2 receptor, antagonist for leukotriene receptor,    steroid agent, alpha-adrenergic receptor stimulator, xanthine    derivative, anticholinergic agent, and nitric oxide synthase    inhibitor.-   16. Use of the compound represented by formula (I) according to 1    above, a salt thereof, a solvate thereof, or a prodrug thereof for    the production of a pharmaceutical composition for prevention and/or    treatment of diseases mediated by DP receptor.-   17. Use of the compound represented by formula (I) according to 1    above, a salt thereof, a solvate thereof, or a prodrug thereof for    the production of an antagonist of DP receptor.-   18. A method for prevention and/or treatment of diseases mediated by    DP receptor, which comprises administering to a mammal an effective    amount of the compound represented by formula (I) according to 1    above, a salt thereof, a solvate thereof, or a prodrug thereof.

In the present specification, C1-4 alkyl includes linear and branchedalkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl.

In the present specification, C1-6 alkyl includes linear and branchedalkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, andisohexyl.

In the present specification, C2-4 alkenyl includes linear and branchedalkenyl such as ethenyl, propenyl, and butenyl.

In the present specification, C1-6 alkoxy includes linear and branchedalkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, and isohexyloxy.

In the present specification, C1-10 alkoxy includes linear and branchedalkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, anddecyloxy.

In the present specification, C2-6 acyl includes linear and branchedacyl such as ethanoyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, hexanoyl,2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl,2-ethylbutanoyl, and 2,3-dimethylbutanoyl.

In the present specification, a halogen atom includes such as a fluorineatom, a chlorine atom, a bromine atom, and an iodine atom.

In the present specification, trihalomethyl is methyl substituted bythree halogen atoms.

In the present specification, C1-4 alkylene includes linear or branchedalkylene such as methylene, ethylene, propylene, isopropylene,butylenes, and isobutylene.

In the present specification, C2-4 alkenylene includes linear orbranched alkenylene such as vinylene, propenylene, 1- or 2-butenylene,and butadienylene. In the present specification, C2-4 alkynyleneincludes linear or branched alkynylene such as ethynylene, 1- or2-propynylene and 1- or 2-butynylene.

In the present specification, C1-6 alkylene containing 0 to 2 heteroatom(s) selected from a nitrogen atom, an oxygen atom, and a sulfur atomincludes linear or branched alkylene such as: methylene, ethylene,propylene, isopropylene, butylene, isobutylene, pentylene, and hexylene,or linear or branched C1-6 alkylene in which one or two carbon atom(s)in methylene, ethylene, propylene, isopropylene, butylene, isobutylene,pentylene, and hexylene is/are substituted by one or two hetero atom(s)selected from a nitrogen atom (a residual bond in the said nitrogen atombinds to a hydrogen atom, C1-6 alkyl, C2-6 acyl, or C1-6 alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.)), anoxygen atom, and a sulfur atom, e.g., linear or branched C1-6 alkylenecontaining one or two hetero atom(s) selected from a nitrogen atom, anoxygen atom, and a sulfur atom in —(CH₂)₂—NH—, —CH₂)₂—N(CH₃)—,—(CH₂)₂—O—, —(CH₂)₂—S—, —(CH₂)₃—NH—, —CH₂)₃—N(CH₃)—,—CH₂—CH(CH₃)—CH₂—NH—, —CH₂—CH(CH₃)—CH₂—N(CH₃)—, —(CH₂)₃—O— and—(CH₂)₃—S—, wherein only a carbon atom in the alkylene binds to anadjacent —O—.

In the present specification, C2-6 alkenylene having 0 to 2 heteroatom(s) selected from a nitrogen atom, an oxygen atom, and a sulfur atomincludes linear or branched alkenylene such as vinylene, propenylene, 1-or 2-butenylene, butadienylene, pentenylene and hexenylene, or C2-6alkenylene in which one or two carbon atom(s) in vinylene, propenylene,1- or 2-butenylene, butadienylene, pentenylene, and hexenylene is/aresubstituted with one or two hetero atom(s) selected from a nitrogen atom(a residual bond in the said nitrogen atom binds to a hydrogen atom,C1-6 alkyl, C2-6 acyl, or the C1-6 alkoxycarbonyl (e.g., methoxycarbonyland ethoxycarbonyl, tert-butoxycarbonyl etc.)), an oxygen atom, and asulfur atom, e.g., linear or branched C2-6 alkenylene containing one ortwo hetero atom(s) selected from a nitrogen atom, an oxygen atom, and asulfur atom in —CH═CH—NH—, —CH═CH—N(CH₃)—, —CH═CH—O—, —CH═CH—S—,—CH═CH—CH₂—NH—, —CH═CH—CH₂—N(CH₃)—, —CH═CH—CH₂—O—, and —CH═CH—CH₂—S—,wherein only a carbon atom in the alkenylene binds to an adjacent —O—.

In the present specification, C2-6 alkynylene having 0 to 2 heteroatom(s) selected from an nitrogen atom, an oxygen atom, and a sulfuratom includes linear or branched alkynylene such as ethynylene, 1- or2-propynylene, 1- or 2-butynylene, pentynylene, and hexynylene or C2-6alkynylene in which one or two carbon atom(s) in ethynylene, 1- or2-propynylene, 1- or 2-butynylene, pentynylene, hexynylene, andhexenylene is/are substituted with one or two hetero atom(s) selectedfrom a nitrogen atom (a residual bond in the said nitrogen atom binds toa hydrogen atom, C1-6 alkyl, C2-6 acyl, or the C1-6 alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.)), anoxygen atom, and a sulfur atom, e.g., linear or branched C2-6 alkynylenecontaining one or two hetero atom(s) selected from a nitrogen atom, anoxygen atom, and a sulfur atom in —C≡C—NH—, —C≡C—N(CH₃)—, —C≡C—O—,—C≡C—S—, —C≡C—CH₂—NH—, —C≡C—CH₂—N(CH₃)—, —C≡C—CH₂—O—, and —C≡C—CH₂—S—,wherein only a carbon atom in the alkenylene binds to an adjacent —O—.

In the present specification, oxidized C1-6 alkyl includes C1-6 alkylsubstituted by 1 to 3 hydroxyl group(s) and/or 1 to 3 oxo group(s),wherein the carbon atom to which two or more hydroxyl groups and/or oxogroups bind is limited to the carbon atom in the terminal position, suchas hydroxymethyl, formyl, carboxy, 2-hydroxyethyl, 2-oxoethyl,carboxymethyl, 1-hydroxyethyl, acetyl, 3-hydroxypropyl, 3-oxopropyl,2-carboxyethyl, 2-hydroxypropyl, 2-oxopropyl, 1-hydroxy-1-methylethyl,4-hydroxybutyl, 4-oxobutyl, 3-carboxypropyl, 3-hydroxybutyl, 3-oxobutyl,3-hydroxy-2-methylpropyl, 2-methyl-3-oxopropyl, 2-carboxypropyl,2-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl,1-methyl-3-oxopropyl, 2-carboxy-1-methylethyl, 2-hydroxy-1-methylpropyl,1-methyl-2-oxopropyl, 1-hydroxy-1-methylpropyl, 1-hydroxymethylpropyl,1-formylpropyl, 1-carboxypropyl, 2-hydroxy-1,1-dimethylethyl,1,1-dimethyl-2-oxoethyl, and 1-carboxy-1-methylethyl etc.

In the present specification, C1-4 alkyl that may be oxidized includesC1-4 alkyl that may be substituted by 1 to 3 hydroxyl group(s) and/or 1to 3 oxo group(s), wherein the carbon atom to which two or more hydroxylgroups and/or oxo groups bind is limited to the carbon atom in theterminal position, such as linear or branched C1-4 alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl,hydroxymethyl, formyl, carboxy, 2-hydroxyethyl, 2-oxoethyl,carboxymethyl, 1-hydroxyethyl, acetyl, 3-hydroxypropyl, 3-oxopropyl,2-carboxyethyl, 2-hydroxypropyl, 2-oxopropyl, 1-hydroxy-1-methylethyl,4-hydroxybutyl, 4-oxobutyl, 3-carboxypropyl, 3-hydroxybutyl, 3-oxobutyl,3-hydroxy-2-methylpropyl, 2-methyl-3-oxopropyl, 2-carboxypropyl,2-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl,1-methyl-3-oxopropyl, 2-carboxy-1-methylethyl, 2-hydroxy-1-methylpropyl,1-methyl-2-oxopropyl, 1-hydroxy-1-methylpropyl, 1-hydroxymethylpropyl,1-formylpropyl, 1-carboxypropyl, 2-hydroxy-1,1-dimethylethyl,1,1-dimethyl-2-oxoethyl, 1-carboxy-1-methylethyl, etc.

In the present specification, a protective group in “hydroxyl that maybe protected” and “amino that may be protected” includes, e.g., alkylthat may have substituents, carbocyclic ring that may havesubstituent(s), heterocycle that may have substituent(s), alkylsulfonyl(e.g., C1-4 alkylsulfonyl etc., such as methylsulfonyl, ethylsulfonyl,etc.), aromatic ring sulfonyl (e.g., C6-10 aromatic ring sulfonyl etc.,such as phenylsulfonyl etc.), acyl groups, etc. Alkyl in “alkyl that mayhave substituent(s)” includes, e.g, linear or branched C1-20 alkyl suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, nonadecyl, icosyl, etc. Here, the substituent in “alkyl thatmay have substituent(s)” includes hydroxyl, amino, carboxy, nitro,azide, mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino,propylamino, dimethylamino, diethylamino, etc.), N-aromatic ring-aminogroup (e.g., N-phenylamino etc.), N-aromatic ring-N-alkylamino group(e.g., N-phenyl-N-methylamino, N-phenyl-N-ethylamino,N-phenyl-N-propylamino, N-phenyl-N-butylamino, N-phenyl-N-pentyl amino,N-phenyl-N-hexyl amino, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, hexyloxy, etc.), C3-7 cycloalkyl-C1-6 alkoxy group(e.g., cyclohexylmethyloxy, cyclopentylethyloxy, etc.), C3-7cycloalkyloxy (e.g., cyclohexyloxy etc.), C7-15 aralkyloxy (e.g.,benzyloxy, phenethyoxy, phenylpropyloxy, naphthylmethyloxy,naphthylethyloxy, etc.), phenoxy, C1-6 alkoxycarbonyl (e.g.,tert-methoxycarbony, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-4alkylthio (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), ahalogen atom (a fluorine atom, a chlorine atom, a bromine atom, and aniodine atom), alkylsulfonyl (e.g., C1-4 alkylsulfonyl etc., such asmethylsulfonyl, ethylsulfonyl, etc.), aromatic ring-sulfonyl group(e.g., C6-10 aromatic ring-sulfonyl group etc., such as phenylsulfonyletc.), acyl (e.g., C1-6 alkanoyl etc., such as formyl, acetyl,propanoyl, and pivaloyl, and C6-10 aromatic ring-carbonyl group etc.,such as benzoyl etc.), etc. The alkyl may be substituted by 1 to 4arbitrary substituent(s) in the replaceable position. The carbocyclicring in “carbocyclic ring that may have substituent(s)” includes C3-15monocyclic, dicyclic, or tricyclic aromatic carbocyclic ring that may besaturated either wholly or partially.

C3-15 monocyclic, dicyclic, or tricyclic aromatic carbocyclic ring thatmay be saturated either wholly or partially includes cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane,cyclotetradecane, cyclopentadecane, cyclopropene, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene,azulene, perhydroazulene, perhydropentalene, indene, perhydroindene,indane, naphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene,acenaphthene, fluorene, phenalene, phenanthrene, anthracene, etc.

C3-15 monocyclic, dicyclic, or tricyclic aromatic carbocyclic ring thatmay be saturated either wholly or partially includes bicycliccarbocyclic ring containing spiro bond and constructed bicycliccarbocyclic ring such as spiro[4.4]nonane, spiro[4.5]decane,spiro[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene,bicyclo[3.1.1]heptane, bicyclo[3.3.1]hept-2-ene, bicyclo[2.2.2]octane,bicyclo[2.2.2]oct-2-ene, adamantine, noradamantane ring, etc.

Here, the substituent in “carbocyclic ring that may have substituent(s)”includes C1-8 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.),hydroxyl, amino, carboxyl, nitro, mono- or di-C1-6 alkylamino (e.g.,methylamino, ethylamino, propylamino, dimethylamino, diethylamnino,etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.),C1-6 alkoxycarbonyl (e.g., tert-methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, etc.), C1-6 alkylcarbonyloxy (e.g., acetoxy,ethylcarbonyloxy, etc.), C1-4 alkylthio (e.g., methylthio, ethylthio,propylthio, butylthio, etc.), halogen atom (fluoro atom, chloro atom,bromo atom, and iodo atom), trihalomethyl (e.g., trifluoromethyl etc.),etc. The carbocyclic ring may be substituted by 1 to 4 arbitrarysubstituent(s) in the replaceable position. The heterocycle in“heterocycle that may have substituent(s)” includes 3- to 15-memberedmonocyclic, dicyclic, or tricyclic aromatic heterocycle that may besaturated either wholly or partially, containing 1 to 5 hetero atom(s)selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Among3- to 15-membered monocyclic, dicyclic, or tricyclic heterocycle thatmay be saturated either wholly or partially containing 1 to 5 heteroatom(s) selected from an oxygen atom, a nitrogen atom or a sulfur atom,3- to 15-membered monocyclic, dicyclic, or tricyclic aromaticheterocycle containing 1 to 5 hetero atom(s) selected from an oxygenatom, a nitrogen atom, or a sulfur atom includes, e.g., pyrrole,imidazole, triazole, tetrazole, pyrazol, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiin,thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole,oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine,thiadiazine, thiazepine, thiadiazepin, indole, isoindole, indolizine,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene,dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine,purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline,cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene,benzoxepin, benzoxazepine, benzoxadiazepine, benzothiepine,benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine,benzofurazan, benzothiadiazole, benzotriazole, carbazole,beta-carboline, acridine, phenazine, dibenzofuran, xanthene,dibenzothiophene, phenothiazine, phenoxazine, phenoxathiine,thianthrene, phenanthridine, phenanthroline, perimidine ring, etc. Among3- to 15-membered monocyclic, dicyclic, or tricyclic heterocycle thatmay be saturated either wholly or partially containing 1 to 5 heteroatom(s) selected from an oxygen atom, a nitrogen atom or a sulfur atom,3- to 15-membered monocyclic, dicyclic, or tricyclic heterocycle thatwas saturated either wholly or partially containing 1 to 5 heteroatom(s) selected from an oxygen atom, a nitrogen atom or a sulfur atomincludes aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazin, tetrahydropyridazine, perhydropyridazine,dihydroazepine; tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene,tetrahydrothiophene, dihydrothiin(dihydrothiopyran),tetrahydrothiin(tetrahydrothiopyran), dihydrothiepin, tetrahydrothiepin,perhydrothiepin, dihydrooxazole, tetrahydrooxazole(oxazolidine),dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydroxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepin, tetrahydrothiadiazepin, perhydrothiadiazepin,morpholine, thiomorpholine, oxathiane, indoline, isoindolin,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrodibenzothiophene,dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzooxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzooxazepine,tetrahydrobenzooxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindan, benzodioxan, chroman, benzodithiolane,and benzodithiane ring, etc. Here, the substituent in “heterocycle thatmay have substituent(s)” includes C1-8 alkyl (e.g., methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, heptyl, octyl, etc.), hydroxyl, amino, carboxyl, nitro, mono- ordi-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy,propoxy, hexyloxy, etc.), C1-6 alkoxycarbonyl (e.g.,tert-methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-6alkylcarbonyloxy (e.g., acetoxy, ethylcarbonyloxy, etc.), C1-4 alkylthio(e.g., methylthio, ethylthio, propylthio, butylthio, etc.), a halogenatom (a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom), triharomethyl (e.g., trifluoromethyl etc.), etc. The heterocyclemay be substituted by 1 to 4 arbitrary substituent(s) in the replaceableposition. The acyl includes (1) alkylcarbonyl that may havesubstituent(s), (2) alkenylcarbonyl that may have substituent(s), (3)alkynylcarbonyl that may have substituent(s), (4) carbocyclic carbonylgroup that may have substituent(s), (5) heterocyclic carbonyl group thatmay have substituent(s). The acyl may be substituted by 1 to 4 arbitrarysubstituent(s) in the replaceable position. The alkyl that may havesubstituent(s) in “alkylcarbonyl that may have substituent(s)” means thesame as “alkyl that may have the substituent(s)”. The alkenyl that mayhave substituent(s) in “alkenylcarbonyl that may have substituent(s)”includes, e.g., linear or branched C2-20 alkenyl group etc., such asethenyl, propenyl, butenyl, pentenyl, hexenyl, etc. Here, thesubstituent in the alkenyl means the same as the substituent in theaforementioned “alkyl that may have substituent(s)”. The alkynyl thatmay have substituent(s) in “alkynylcarbonyl that may havesubstituent(s)” includes, e.g., linear or branched C2-20 alkynyl groupetc., such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Here,the substituent in the alkynyl means the same as the substituent in theaforementioned “alkynyl that may have substituent(s)”. The carbocyclicring that may have substituent(s) in “carbocyclic carbonyl group thatmay have substituent(s)” means the same as the aforementioned“carbocyclic ring that may have substituent(s)”. The carbocyclic ringthat may have substituent(s) in “heterocyclic carbonyl that may havesubstituent(s)” means the same as the aforementioned “carbocyclic ringthat may have substituent(s)”.

In the present specification, the substituent in “phenyl that may havesubstituent(s)” includes C1-8 alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, etc.), hydroxyl, amino, carboxyl, nitro, mono- or di-C1-6alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino,diethylamino, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy,hexyloxy, etc.), C1-6 alkoxycarbonyl (e.g., tert-methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-6 alkylcarbonyloxy (e.g.,acetoxy, ethylcarbonyloxy, etc.), C1-4 alkylthio (e.g., methylthio,ethylthio, propylthio, butylthio, etc.), a halogen atom (a fluorineatom, a chlorine atom, a bromine atom, and an iodine atom),trihalomethyl (e.g., trifluoromethyl etc.), etc. The phenyl may besubstituted by 1 to 4 arbitrary substituent(s) in the replaceableposition. In the present specification, the substituent in “pyridyl thatmay have substituent(s)” includes C1-8 alkyl (e.g., methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, heptyl, octyl, etc.), hydroxyl, amino, carboxyl, nitro, mono- ordi-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy,propoxy, hexyloxy, etc.), C1-6 alkoxycarbonyl (e.g.,tert-methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-6alkylcarbonyloxy (e.g., acetoxy, ethylcarbonyloxy, etc.), C1-4 alkylthio(e.g., methylthio, ethylthio, propylthio, butylthio, etc.), a halogenatom (a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom), trihalomethyl (e.g., trifluoromethyl etc.), etc. The pyridyl maybe substituted by 1 to 4 arbitrary substituent(s) in the replaceableposition.

In the present specification, the C2-5 alkylene in which the carbon atommay replace an oxygen atom, a nitrogen atom, or a sulfur atom includeslinear or branched C2-5 alkylene such as ethylene, propylene,iso-propylene, butylene, iso-butylene, pentylene, etc., C2-5 alkylene,etc., in which the carbon atom in ethylene, propylene, iso-propylene,butylene, iso-butylene, or pentylene may be replaced with an oxygenatom, a nitrogen atom, or a sulfur atom.

The residual bond in the nitrogen atom binds to a hydrogen atom, C1-6alkyl, C2-6 acyl, or C1-6 alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, etc.). The C2-5 alkylene may besubstituted by substituent(s). Here, the substituent includes C1-8 alkyl(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl, amino,carboxyl, nitro, mono- or di-C1-6 alkylamino (e.g., methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.), C1-6 alkoxy(e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.), C1-6 alkoxycarbonyl(e.g., tert-methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.),C1-6 alkylcarbonyloxy (e.g., acetoxy, ethylcarbonyloxy, etc.), C1-4alkylthio (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), ahalogen atom (a fluorine atom, a chlorine atom, a bromine atom, and aniodine atom), trihalomethyl (e.g., trifluoromethyl etc.), etc. The C2-5alkylene may be substituted by 1 to 4 arbitrary substituent(s) in thereplaceable position.

The C2-5 alkylene includes, e.g., —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —O—CH₂—, —O—(CH₂)₂—, —O—(CH₂)₃—, —O—(CH₂)₄—, —CH₂—O—CH₂—,—CH₂—O—(CH₂)₂—, —CH₂—O—(CH₂)₃—, —(CH₂)₂—O—(CH₂)₂—, —NH—CH₂—,—NH—(CH₂)₂—, —NH—(CH₂)₃—, —NH—(CH₂)₄—, —CH₂—NH—CH₂—, —CH₂—NH—(CH₂)₂—,—CH₂—NH—(CH₂)₃—, —(CH₂)₂—NH—(CH₂)₂—, —N(CH₃)—CH₂—, —N(CH₃)—(CH₂)₂—,—N(CH₃)—(CH₂)₃—, —N(CH₃)—(CH₂)₄—, —CH₂—N(CH₃)—CH₂—, —CH₂—N(CH₃)—(CH₂)₂—,—CH₂—N(CH₃)—(CH₂)₃—, —(CH₂)₂—N(CH₃)—(CH₂)₂—, —S—CH₂—, —S—(CH₂)₂—,—S—(CH₂)₃—, —S—(CH₂)₄—, —CH₂—S—CH₂—, —CH₂—S—(CH₂)₂—, —CH₂—S—(CH₂)₃—,—(CH₂)₂—S—(CH₂)₂—, etc.

In the present specification, the C2-5 alkenylene in which the carbonatom may replace an oxygen atom, a nitrogen atom, or a sulfur atomincludes linear or branched C2-5 alkenylene such as vinylene,propenylene, iso-propenylene, butenylene, iso-butenylene, pentenylene,etc., or C2-5 alkenylene etc., in which the carbon atom in vinylene,propenylene, iso-propenylene, butenylene, iso-butenylene, or pentenylenereplaces an oxygen atom, a nitrogen atom, or a sulfur atom. The residualbond in the nitrogen atom binds to a hydrogen atom, C1-6 alkyl, C2-6acyl, or C1-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, etc.). The C2-5 alkenylene may be substituted bysubstituent(s). Here, the substituent includes C1-8 alkyl (e.g., methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, heptyl, octyl, etc.), hydroxyl, amino, carboxyl, nitro,mono- or di-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy,propoxy, hexyloxy, etc.), C1-6 alkoxycarbonyl (e.g.,tert-methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-6alkylcarbonyloxy (e.g., acetoxy, ethylcarbonyloxy, etc.), C1-4 alkylthio(e.g., methylthio, ethylthio, propylthio, butylthio, etc.), a halogenatom (a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom), trihalomethyl (e.g., trifluoromethyl etc.), etc. The C2-5alkenylene may be substituted by 1 to 4 arbitrary substituent(s) in thereplaceable position. The C2-5 alkenylene includes, e.g., —CH═CH—CH═CH—,—CH═CH—CH═N—, —CH═CH—NH—, —CH═CH—S—, —CH═CH—O—, —N═CH—NH—, etc.

In the present specification, the C1-6 alkylidene in “C1-6 alkylidenemay be substituted” includes, e.g., methylidyne, ethylidene,propylidene, butylidene, pentylidene, hexylidene, etc. Here, thesubstituent in “C1-6 alkylidene may be substituted” includes hydroxyl,amino, carboxyl, nitro, azido, mono- or di-C1-6 alkylamino (e.g.,methylamino, ethylamino, propylamino, dimethylamino, diethylamino,etc.), N-aromatic ring-amino group (e.g., N-phenylamino etc.),N-aromatic ring-N-alkylamino group (e.g., N-phenyl-N-methylamino,N-phenyl-N-ethylamino, N-phenyl-N-propylamino, N-phenyl-N-butylamino,N-phenyl-N-pentyl amino, N-phenyl-N-hexyl amino, etc.), C1-6 alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C3-7cycloalkyl-C1-6, alkoxy (e.g., cyclohexylmethyloxy, cyclopentylethyloxy,etc.), C3-7 cycloalkyloxy (e.g., cyclohexyloxy etc.), C7-15 aralkyloxy(e.g., benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethyloxy,naphthylethyloxy, etc.), phenoxy, C1-6 alkoxycarbonyl (e.g.,tert-methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), C1-6alkylcarbonyloxy (e.g., acetoxy, ethylcarbonyloxy, etc.), C1-4 alkylthio(e.g., methylthio, ethylthio, propylthio, butylthio, etc.), a halogenatom (a fluorine atom, a chlorine atom, a bromine atom, and an iodineatom), alkylsulfonyl (e.g., C1-4 alkylsulfonyl etc., such asmethylsulfonyl, ethylsulfonyl, etc.), aromatic ring-sulfonyl (e.g.,C6-10 aromatic ring sulfonyl etc., such as phenylsulfonyl etc.), acyl(e.g., C1-6 alkanoyl etc., such as formyl, acetyl, propanoyl, pivaloyl,etc., and C6-10 aromatic ring carbonyl etc., such as benzoyl etc.) etc.The C1-6 alkylidene may be substituted by 1 to 4 arbitrarysubstituent(s) in the replaceable position.

In the present specification, the C5-12 monocyclic or bicycliccarbocyclic ring includes a monocyclic or bicyclic C5-12 carbocyclicring aryl or carbocyclic ring which is saturated either wholly orpartially such as cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene,cycloheptadiene, benzene, pentalene, perhydropentalene, azulene,perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene.

In the present specification, the 5- to 12-membered monocyclic orbicyclic heterocycle includes a 5- to 12-membered monocyclic or bicyclicheterocyclic aryl containing hetero atom(s) selected from 1 to 4nitrogen atom(s), one or two oxygen atom(s) and/or one or two sulfuratom(s) and the heterocycle that is saturated either wholly orpartially. Such heterocycle includes, e.g., pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene,thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, oxazine,thiazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline,quinolidine, phthalazine, naphthylidine, quinoxaline, quinazoline,cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene,benzoxepine, benzoxazepine, benzothiepine, benzothiazepine,benzoazepine, benzodiazepine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, dihydrothiophene,tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazole,tetrahydrooxazole(oxazolidine), dihydroisoxazole,tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrothiazine, tetrahydrothiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine; tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathian, dihydrobenzoxazine,dihydrobenzothiazine, dihydrobenzoxazole, perhydrobenzoxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepan,dihydrobenzoxazepine, and tetrahydrobenzoxazepine.

In the present specification, the C5-6 saturated carbocyclic ringincludes cyclopentane and cyclohexane.

In the present specification, the 5- to 6-membered saturated heterocyclecontaining one or two nitrogen atom(s), one or two oxygen atom(s) and/ora sulfur atom includes, e.g., pyrrolidine, imidazolidine, pyrazolidine,piperidine, piperazine, perhydropyrimidine, perhydropyridazine,tetrahydrofuran, tetrahydropyran, tetrahydrothiophene,tetrahydrothiopyran, tetrahydrooxazole(oxazolidine),tetrahydroisoxazole(isoxazolidine), tetrahydrothiazole(thiazolidine),tetrahydroisothiazole(isothiazolidine), tetrahydrooxazine,tetrahydrothiazine, morpholine, thiomorpholine, oxathiane, dioxolane,dioxane, etc. In the present specification, the C5-6 carbocyclic ringincludes, e.g., cyclopentane, cyclohexane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene, benzene, etc.

In the present specification, the 5- to 6-membered heterocyclecontaining one or two nitrogen atom(s), one or two oxygen atom(s) and/ora sulfur atom includes, e.g., pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran,oxazole, isoxazole, thiazole, isothiazole, oxazine, thiazine, pyrroline,pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydroxazole,tetrahydroxazole(oxazolidine), dihydroisoxazole,tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydroxazine, tetrahydroxazine,dihydrothiazine, tetrahydrothiazine, morpholine, thiomorpholine,oxathiane, dioxolane, dioxane, etc.

In the present specification, the substituent in the phenyl that may besubstituted means the same as the substituent in the alkyl that may besubstituted.

In the present specification, the sulfur atom that may be oxidizedincludes sulfone, sulfoxide, and sulfide.

Unless otherwise specifically mentioned, all isomers are included in thepresent specification. For example, linear and branched alkyl, alkenyl,alkynyl, alkoxy, alkylthio, alkylene, alkenylene, and alkynylene areincluded. Further, all of isomers due to double bond, ring and fusedring (E-, Z-, cis- and trans-substances), isomers due to presence ofasymmetric carbon etc. (R-, S-, α- and β-substances, enantiomer, anddiastereomer), optically active substances having optical rotation (D-,L-, d-, and l-substances), polar substances by chromatographicseparation (high-polar substance and low-polar substance), equilibriumcompounds, rotational isomers, a mixture thereof in any proportion and aracemic mixture are included in the present invention.

Unless otherwise specifically mentioned in the present specification, aswill be obvious for persons skilled in the art, a symbol

means a bond to the opposite side of the paper (i.e., α-configuration),

means a bond to this side of the paper (i.e., β-configuration),

means α-configuration, β-configuration, or a mixture thereof, and

means α-configuration or β-configuration.

The compounds represented by formula (I) are converted to salts by knownmethods. The salts include alkali metal salt, alkaline earth metal salt,ammonium salt, amine salt, acid addition salt, etc. The salts arepreferably pharmaceutically acceptable.

The salts are preferably water-soluble. Appropriate salts are alkalinemetal salt (potassium, sodium, etc.), alkaline earth metal salt(calcium, magnesium, etc.), ammonium salt, organic amine salt that ispharmaceutically acceptable (tetramethylammonium, triethylamine,methylamine, dimethylamine, cyclopentylamine, benzylamine,phenethylamine, piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine,etc.).

The acid addition salts are preferably water-soluble. Appropriate acidaddition salts include inorganic acid salts such as hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, and organicacid salt such as acetate, lactate, tartrate, oxalate, benzoate,citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isothionate, glucuronate, and gluconate.

The compounds represented by formula (I) and salts thereof are convertedto solvates.

The solvates are preferably non-toxic and water-soluble. Appropriatesolvates include solvates such as water and alcoholic solvent (e.g.,ethanol etc.).

The prodrug of the compound represented by formula (I) means a compoundthat is converted to the compound represented by formula (I) by reactionwith enzymes, gastric acid etc in vivo. The prodrug of the compoundrepresented by formula (I) include compounds in which the amino groupwas, e.g., acylated, alkylated, or phosphorylated (e.g., compounds inwhich the amino group of the compound represented by formula (I) waseicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidyimethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, etc.) when the compound representedby formula (I) has an amino group; compounds in which the hydroxyl groupwas, e.g., acylated, alkylated, phosphorylated or borated (e.g.,compounds in which the hydroxyl group of the compound represented byformula (I) was acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, ordimethylaminomethylcarbonylated) when the compound represented byformula (I) has a hydroxyl group; the carboxyl group of the compoundrepresented by formula (I) was, e.g., esterified or amidated (e.g.,compounds in which the carboxyl group of the compound represented byformula (I) was made into ethyl ester, phenyl ester, phenylethyl ester,carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide) when the compoundrepresented by formula (I) has a carboxy group; compounds in which thecarboxy group replaces with hydroxymethyl group. Those compounds may beproduced by a known method per se. The prodrug of the compoundrepresented by formula (I) may be either a hydrate or a non-hydrate.

R¹ in formula (I) is preferably a hydrogen atom, C1-4 alkyl or benzyland, more preferably, a hydrogen atom or C1-4 alkyl.

R² in formula (I) is preferably a halogen atom, C1-6 alkyl, C1-6 alkoxy,hydroxyl, trihalomethyl, cyano, phenyl, pyridyl, nitro, or NR⁶R⁷ andmore preferably a halogen atom, C1-6 alkyl, C1-6 alkoxy, or hydroxyl.

R³ in formula (I) is preferably a halogen atom, C1-6 alkyl, C1-6 alkoxy,hydroxyl, trihalomethyl, or cyano, and more preferably a halogen atom,C1-6 alkyl, C1-6 alkoxy, or trihalomethyl.

R⁸ in formula (I) is preferably C1-4 alkyl or phenyl.

R⁴ in formula (I) is preferably a hydrogen atom, C1-4 alkyl or benzyl,and more preferably a hydrogen atom or C1-4 alkyl.

R⁵ in formula (I) is preferably C1-6 alkyl, C1-10 alkoxy, a halogenatom, hydroxyl, trihalomethyl, phenyl or cyano, and more preferably C1-6alkyl, C1-10 alkoxy, or a halogen atom.

R¹² in formula (I) is preferably C1-4 alkyl, a halogen atom, hydroxylwhich may be protected, or a hydrogen atom, and more preferably C1-4alkyl or a halogen atom.

R¹³ in formula (I) is preferably C1-4 alkyl, a halogen atom, hydroxylwhich may be protected, or a hydrogen atom, and more preferably C1-4alkyl or a halogen atom.

A group represented by a combination with R¹² and R¹³ in formula (I) ispreferably a group in which either is one except a hydrogen atom, andmore preferably a group in which both are one except a hydrogen atom.

The group represented by the combination with R¹² and R¹³ in formula (I)is preferably oxo or C2-5 alkylene in which one carbon atom may bereplaced with an oxygen atom, a nitrogen atom, or a sulfur atom, andmore preferably oxo, ethylene, or —(CH₂)₂—O—(CH₂)₂—.

in formula (I) is preferably C5-6 monocyclic carbocyclic ring or 5- to6-membered monocyclic heterocycle containing one or two nitrogenatom(s), one or two oxygen atom(s) and/or a sulfur atom such ascyclopentane, cyclohexane, benzene, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene,thiopyran, oxazole, isoxazole, thiazole, isothiazole, pyrrolidine,imidazolidine, piperidine, or piperazine ring, and is more preferablybenzene or pyridine ring.

It is furthermore preferably C5-6 monocyclic carbocyclic ring such asbenzenes represented by

in formula (I) is preferably

(in the formula, all symbols present the same meanings as theaforementioned) and is more preferably

(in the formula, all symbols present the same meanings as theaforementioned, wherein two R³'s may be same or different.).

G in formula (I) is preferably (1) C1-6 alkylene containing 0 to 2hetero atom(s) selected from a nitrogen atom, an oxygen atom, and asulfur atom, (2) C2-6 alkenylene or (3) C2-6 alkynylene and is morepreferably (1) C1-6 alkylene containing 0 to 2 hetero atom(s) selectedfrom a nitrogen atom, an oxygen atom, and a sulfur atom, (2) C2-4alkenylene or (3) C2-4 alkynylene, and is furthermore preferably (1)C1-4 alkylene, (2) C2-4 alkenylene, or (3) C2-4 alkynylene.

in formula (I) is preferably

(in the formula,

is C5-6 saturated carbocyclic ring or 5- to 6-membered saturatedheterocycle containing one or two nitrogen atom(s), one or two oxygenatom(s) and/or a sulfur atom; and

is C5-6 carbocyclic ring or 5- to 6-membered heterocycle containing oneor two nitrogen atom(s), one or two oxygen atom(s) and/or a sulfuratom.).

is preferably 5- to 6-membered saturated heterocycle containing one ortwo nitrogen atom(s), one or two oxygen atom(s) and/or a sulfur atom,and is more preferably 5- to 6-membered saturated heterocycle containingone or two nitrogen atom(s) and/or one or two oxygen atom(s). Forexample, it is preferably morpholine, dioxane, oxathiane,tetrahydrofuran, pyrrolidine, tetrahydrooxazole(oxazolidine), orimidazolidine and is more preferably morpholine, tetrahydrofuran, orpyrrolidine.

is preferably C5-6 carbocyclic ring or 5- to 6-membered heterocyclecontaining one or two nitrogen atom(s) and/or one or two oxygen atom(s),and more preferably a C5-6 carbocyclic ring or a 5- to 6-memberedheterocycle containing one or two nitrogen atom(s). For example, it ispreferably cyclopentane, cyclohexane, cyclopentadiene, benzene,pyridine, pyrazine, pyrimidine, pyridazine, oxazine, piperidine, orpiperazine and is more preferably cyclohexane, benzene, pyridine,pyrazine, or pyrimidine ring, and is furthermore preferably benzene.

is preferably dihydrobenzoxazine, benzodioxane, benzoxathiane,dihydrobenzofuran, or indoline and more preferably dihydrobenzoxazine,dihydrobenzofuran, or indoline, and furthermore preferablydihydrobenzoxazine.

is preferably dihydrobenzoxazin-2-yl, benzodioxan-2-yl,benzoxathian-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl,benzodioxol-2-yl, indolin-2-yl, or indolin-3-yl, and is more preferablydihydrobenzoxazin-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl,indolin-2-yl, or indolin-3-yl, and is furthermore preferablydihydrobenzoxazin-2-yl.

Symbol “m” is preferably 0, 1, or 2.

Symbol “n” is preferably 2, 3, or 4, and is more preferably 2.

Symbol “i” is preferably 0 or an integer of 1 to 5.

With regard to the compound represented by formula (I), a preferredcompound is a compound represented by formula (I-a)

wherein all symbols have the same meanings as the aforementioned, acompound represented by formula (I-b)

wherein all symbols have the same meanings as the aforementioned, or acompound represented by formula (I-c)

wherein all symbols have the same meanings as the aforementioned.

As concrete compounds, the present invention includes

-   (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,3    dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4    -dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (5-((2,6    dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetic    acid,-   (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic    acid,-   (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((4-(1,3-benzodioxol-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic    acid,-   (3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-difluorobenzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((2,5-difluoro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)acetic    acid,-   (5-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-difluorobenzoyl)amino)-2-fluorophenyl)acetic    acid,-   (4-chloro-3-((2,6-dichloro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-chloro-5-((2,5-dichloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((2,3-dichloro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluoro-6-methylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-methylbenzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((2-fluoro-3-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-fluoro-2-methylbenzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-fluoro-5-((3-fluoro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)acetic    acid,-   (5-((2-chloro-4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-6-methylbenzoyl)amino)-2-fluorophenyl)acetic    acid,-   (4-chloro-3-((2-chloro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-methylbenzoyl)amino)phenyl)acetic    acid,-   (3-chloro-5-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-3-methylbenzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((5-chloro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)acetic    acid,-   (3-((3-chloro-4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2-chloro-6-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((2-chloro-4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-5-fluorobenzoyl)amino)-2-methylphenyl)acetic    acid,-   (3-((2-chloro-3-fluoro-4-(((2S)-6-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((5-chloro-2-fluoro-4-(((2S)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)acetic    acid,-   (5-((3-chloro-4-(((2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-fluorobenzoyl)amino)-2-fluorophenyl)acetic    acid,-   (4-chloro-3-((4-(((2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-chloro-5-((2,5-dimethyl-4-(((2R)-7-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((4-(((2R)-7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((4-(((2R)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((4-(((2R)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-methylphenyl)acetic    acid,-   (3-((4-(((2R)-1-ethyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((4-(((2R)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-fluorophenyl)acetic    acid,-   (5-((4-(((2R)-1-ethyl-5-methyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-2-fluorophenyl)acetic    acid,-   (4-chloro-3-((4-(((2S)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-chloro-5-((4-(((2S)-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (2-chloro-5-((2,3-dimethyl-4-(((2S)-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((4-((3S)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-fluorophenyl)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-5-fluorophenyl)acetic    acid,    (5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-2-fluorophenyl)acetic    acid,-   (3-chloro-5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,    (2-chloro-5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-2-methylphenyl)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   2-(4-fluoro-3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)2-methylpropanoic    acid,-   2-(4-fluoro-3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(4-fluoro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-methyl-2-(4-methyl-3-(2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-methyl-2-(4-methyl-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-methyl-2-(3-methyl-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-methyl-2-(3-methyl-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-(3-fluoro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-fluoro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-fluoro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-methyl-2-(2-methyl-5-(2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-methyl-2-(2-methyl-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(2-fluoro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-fluoro-5-((2-fluoro-4-(((2S)A-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(2-fluoro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-(2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-methyl-2-(3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-methyl-2-(3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((3-chloro-2-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((5-chloro-4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluorobenzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(5-((2-chloro-3-fluoro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-fluorobenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((2-chloro-6-fluoro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((3-chloro-4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((5-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-3-methylbenzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((2-chloro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-(((2R)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-6-methylbenzoyl)amino)-4-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((4-(((2S)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-3-fluoro-2-methylbenzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(2-fluoro-5-((5-fluoro-4-(((2S)-7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-fluoro-5-((2-fluoro-3-methyl-4-(((2R)-7-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-fluoro-3-((2-fluoro-4-(((2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-5-methylbenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((4-(((2R)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-fluoro-6-methylbenzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(5-((2,3-dichloro-4-(((2S)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(3-((2,5-dichloro-4-(((2S)-6-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-5-fluorophenyl)-2-methylpropanoic    acid,-   2-(5-((2,6-dichloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)benzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((4-(((2R)-1-ethyl-5-methyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-difluorobenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-chloro-5-((4-(((2R)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-difluorobenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((4-(((2R)-1-ethyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-difluorobenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(3-((2,5-dimethyl-4-(((2S)-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((4-(((2S)-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   2-(4-fluoro-3-((2-fluoro-4-(((2S)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(3-((2-chloro-4-((3S)-2,3-dihydro-1-benzofuran-3-ylmethoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   2-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-2-fluorophenyl)-2-methylpropanoic    acid,-   2-(2-chloro-5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)-2-methylpropanoic    acid,-   2-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,3-dimethylbenzoyl)amino)-2-methylphenyl)-2-methylpropanoic    acid,-   (3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl)acetic    acid,-   (3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(methyl)amino)phenyl)acetic    acid,-   (3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(ethyl)amino)phenyl)acetic    acid,-   (3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl)acetic    acid,-   (3-chloro-5-(((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylphenyl)sulfonyl)amino)phenyl)acetic    acid,-   (2-chloro-5-(((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylphenyl)sulfonyl)(methyl)amino)phenyl)acetic    acid,-   (3-(((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylphenyl)sulfonyl)(ethyl)amino)-4-methylphenyl)acetic    acid,-   (4-fluoro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic    acid,-   (3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluorobenzoyl)amino)-5-fluorophenyl)(oxo)acetic    acid,-   (5-((2-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)(oxo)acetic    acid,-   (4-chloro-3-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)(oxo)acetic    acid,-   (3-chloro-5-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)(oxo)acetic    acid,-   (2-chloro-5-((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)(oxo)acetic    acid,-   (3-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-methylphenyl)(oxo)acetic    acid,-   (3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-difluorobenzoyl)amino)-5-methylphenyl)(oxo)acetic    acid,-   (5-((2,5-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)(oxo)acetic    acid,-   (3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2-fluoro-3-methylbenzoyl)amino)-4-fluorophenyl)(oxo)acetic    acid,-   (3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-methylbenzoyl)amino)-5-fluorophenyl)(oxo)acetic    acid,-   (5-((3-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-2-fluorobenzoyl)amino)-2-fluorophenyl)(oxo)acetic    acid,-   (3-((2-fluoro-6-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic    acid,-   (3-((2-chloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-5-methylbenzoyl)amino)phenyl)(oxo)acetic    acid,-   (3-((2-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-3-fluorobenzoyl)amino)phenyl)(oxo)acetic    acid,-   (4-chloro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3-chloro-5-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluorobenzoyl)amino)phenyl)(difluoro)acetic    acid,-   (2-chloro-5-((2-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-methylphenyl)(difluoro)acetic    acid,-   difluoro(3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-5-methylphenyl)acetic    acid,-   (5-((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-2-methylphenyl)(difluoro)acetic    acid,-   difluoro(4-fluoro-3-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-difluorobenzoyl)amino)-5-fluorophenyl)(difluoro)acetic    acid,-   (5-((2,5-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)(difluoro)acetic    acid,-   (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2-fluoro-3-methylbenzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3-chloro-5-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)(difluoro)acetic    acid,-   (2-chloro-5-((3-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-2-fluorobenzoyl)amino)phenyl)(difluoro)acetic    acid,-   difluoro(3-((2-fluoro-6-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2-chloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-5-methylbenzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3-((2-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-3-fluorobenzoyl)amino)phenyl)(difluoro)acetic    acid,-   1-(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-fluorophenyl)cyclopropanecarboxylic    acid,-   1-(3-fluoro-5-((4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(5-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-fluorophenyl)cyclopropanecarboxylic    acid,-   1-(4-chloro-3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(3-chloro-5-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(2-chloro-5-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluorobenzoyl)amino)-4-methylphenyl)cyclopropanecarboxylic    acid,-   1-(3-((2,6-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)cyclopropanecarboxylic    acid,-   1-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2-fluoro-5-methylbenzoyl)amino)-2-methylphenyl)cyclopropanecarboxylic    acid,-   1-(3-((2-chloro-3-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)cyclopropanecarboxylic    acid,-   1-(4-chloro-3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-fluorobenzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(3-((2-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-6-methylbenzoyl)amino)-4-methylphenyl)cyclopropanecarboxylic    acid,-   1-(5-((2-chloro-4-((3R)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-5-fluorobenzoyl)amino)-2-fluorophenyl)cyclopropanecarboxylic    acid,-   1-(2-chloro-5-((5-fluoro-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   1-(5-((3-chloro-4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2-methylbenzoyl)amino)-2-methylphenyl)cyclopropanecarboxylic    acid,-   4-(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic    acid,-   4-(4-chloro-3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)tetrahydro-2H-pyran-4-carboxylic    acid,-   4-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2-fluoro-5-methylbenzoyl)amino)-2-methylphenyl)tetrahydro-2H-pyran-4-carboxylic    acid,-   4-(4-chloro-3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-fluorobenzoyl)amino)phenyl)tetrahydro-2H-pyran-4-carboxylic    acid,-   4-(3-((2-chloro-3-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)tetrahydro-2H-pyran-4-carboxylic    acid,-   2-methyl-2-(3-(((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl)propanoic    acid,-   2-methyl-2-(3-(methyl((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl)propanoic    acid,-   (3-(((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl)(difluoro)acetic    acid,-   1-(2-chloro-5-(((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylphenyl)sulfonyl)(methyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (3-(((2-chloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)-5-methylphenyl)(oxo)acetic    acid,-   (3-chloro-5-(((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl)(difluoro)acetic    acid,-   2-(2-chloro-5-(((4-((2R)-2,3-dihydro-1,4-benzodixin-2-ylmethoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl)-2-methylpropanoic    acid,-   (3-((4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (4-chloro-3-((2,6-dimethyl-4-(((2R)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((4-(((2S)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-fluorophenyl)acetic    acid,-   (4-chloro-3-((4-(((2R)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-2,6dimethylbenzoyl)amino)-4-methylphenyl)acetic    acid,-   (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-ethylphenyl)acetic    acid,-   (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-isopropylphenyl)acetic    acid,-   (3-((2-ethyl-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (5-((5-methyl-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methoxyphenyl)acetic    acid, and-   (2-chloro-5-((2,5-dimethoxy-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid, compounds presented in example, salts thereof, solvates    thereof, and prodrugs thereof.

As more preferable compounds, the present invention includes

-   (1)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (2)    (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3)    (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (4)    (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (5)    (4-chloro-3-((2,5-dimethyl-4-((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (6)    (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (7)    (4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (8)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (9)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (10)    (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (11)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (12)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (13)    (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (14)    (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (15)    (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (16)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (17)    (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)acetic    acid,-   (18)    (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (19)    (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)acetic    acid,-   (20)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (21)    (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (22)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (23)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)acetic    acid,-   (24)    (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid,-   (25)    (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (26)    (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (27)    (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (28)    (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (29)    (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (30)    (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (31)    (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (32)    (3-((4-(1,3-benzodioxol-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic    acid etc.

As furthermore preferable compounds, the present invention includes

-   (1)    2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (2)    (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetic    acid,-   (3)    (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic    acid,-   (4)    2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (5)    2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoic    acid,-   (6)    2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoic    acid,-   (7)    1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (8)    1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (9)    1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylic    acid,-   (10)    (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (11) (3-((2,6    dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)acetic    acid etc.

The present invention includes compounds that R¹² and R¹³ in formula (I)simultaneously present hydrogen atoms and that fill at least one underconditions of the following (1)-(6);

-   (1) R² is oxidized C1-6 alkyl, (2) two R² substituted for the    adjacent carbon atom together represent C2-5 alkylene (the said C2-5    alkylene may be substituted by a substituent.) in which the carbon    atom may replace an oxygen atom, a nitrogen atom, or a sulfur atom    that may be oxidized, (3) two R² substituted for the adjacent carbon    atom together represent C2-5 alkenyne (the said C2-5 alkenyne may be    substituted by a substituent.) in which the carbon atom may replace    an oxygen atom, a nitrogen atom, or a sulfur atom that may be    oxidized, (4) R³ is oxidized C1-6 alkyl, (5) R⁴ is oxidized C1-6    alkyl, and (6) R⁵ is oxidized C1-6 alkyl, salts thereof, solvates    thereof, and prodrugs thereof.

Concretely, for example, they include

-   (3-((5-(hydroxymethyl)-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(hydroxymethyl)phenyl)acetic    acid,-   (4-chloro-3-((4-(((3R)-5-(hydroxymethyl)-2,3-dihydro-1-benzofuran-3-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic    acid,-   (3-((5-formyl-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic    acid,-   (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-formylphenyl)acetic    acid,-   (3-((2-chloro-3-fluoro-4-(((2S)-6-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic    acid,-   (5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-(hydroxymethyl)-6-methylbenzoyl)amino)-2-methylphenyl)acetic    acid,-   5-(((3-(carboxymethyl)phenyl)amino)carbonyl)-4-methyl-2-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoic    acid,-   4-(carboxymethyl)-2-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)benzoic    acid, or-   (6-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2,3-dihydro-1H-inden-4-yl)acetic    acid etc.

Since the compounds of the present invention specifically bind to DPreceptors and bind weakly to other prostaglandins receptors, they havethe excellent selectivity. Additionally, the compounds of the presentinvention have the excellent solubility. In physical, chemical, andpharmacological property that is most requested in drug development, thecompounds of the present invention have the requirement for which theybecome very excellent medicines (The Merck Manual of Diagnosis andTherapy (17th Ed.), published by Merck & Co).

Process for Production of the Compounds of the Present Invention

The compounds of the present invention represented by formula (I) can beproduced by known methods, e.g., methods as shown below, methodsaccording to these method, and methods shown in examples. Further, rawmaterial salts can be used in each following process. As such salts, thepharmaceutically allowable salts of the aforementioned formula (I) canbe used.

I. Among the compounds represented by formula (I), the compound in whichR¹ represents C1-4 alkyl, C2-4 alkenyl or benzyl, i.e., thoserepresented by formula (IA)

wherein Q is —C(R¹²)(R¹³)—, R^(1A) is C1-4 alkyl, C2-4 alkenyl orbenzyl, and other symbols have the same meanings as the aforementioned,can be produced according to the process as mentioned below.

(a) The compound in which E represents —C(═O)— or —S(O)₂— in formula(IA), i.e., the compound represented by formula (IA-1)

wherein E^(A) is —C(═O)— or —S(O)₂— and other symbols have the samemeanings as the aforementioned, can be produced by subjecting thecompound represented by formula (II-1)

wherein Q¹ is Q, R²⁻¹ has the same meaning as R², if necessary,carboxyl, hydroxyl, amino, or thiol in the group represented by R²⁻¹ isprotected, R⁴⁻¹ is a hydrogen atom, and other symbols have the samemeanings as aforementioned, or the compound represented by formula(II-2)

wherein R⁴⁻² is C1-6 alkyl or benzyl and other symbols have the samemeanings as the aforementioned, to an amidation reaction with a compoundrepresented by formula (III)

wherein E¹ is —COOH or —SO₃H; G¹, R³⁻¹, and R⁵⁻¹ have the same meaningsas R³, and R⁵, respectively, if necessary, carboxyl, hydroxyl, amino,nitrogen atoms, or thiol in the group represented by G¹, R³⁻¹, and R⁵⁻¹is protected, and other symbols have the same meanings as thoseaforementioned, followed by subjecting to deprotection.

The amidation reaction has been known and its examples are

-   (1) a process using an acid halide,-   (2) a process using a mixed acid anhydride and-   (3) a process using a condensing agent.

Such processes will be specifically illustrated as follows.

(1) A process using an acid halide is carried out, for example, in sucha manner that carboxylic acid is subjected to a reaction with an acidhalide (oxalyl chloride and thionyl chloride etc.) in an organic solvent(chloroform, dichloromethane, diethyl ether, tetrahydrofuran,dimethoxyethane, toluene, etc.) or without solvent at −20° C. torefluxing temperature and the resulting acid halide is subjected to areaction with an amine in the presence of a base (pyridine,triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine, N-methylmorpholine, 5-ethyl-2-methylpyridine(MEP), etc.) in an inert organic solvent (chloroform, dichloromethane,diethyl ether, tetrahydrofuran, etc.) at the temperature of 0 to 40° C.This reaction is preferably carried out under anhydrous condition underinert gas atmosphere (argon and nitrogen etc.). This reaction can becarried out by a reaction the resulting acid halide with an amine in anorganic solvent (dioxane, tetrahydrofuran, dichloromethane, etc.) in thepresence or absence of a phase-transfer catalyst (quaternary ammoniumsalts, e.g., such as tetrabutylammonium chloride, triethylbenzylammoniumchloride, tri-n-octylmethylammonium chloride, trimethyldecylammoniumchloride, tetramethylammonium bromide, etc.) using alkali solution(sodium bicarbonate water and sodium hydroxide solution etc.) at 0 to40° C.

(2) A process using a mixed acid anhydride is carried out, for example,in such a manner that carboxylic acid is made to react with an acidhalide (pivaloyl chloride, tosyl chloride, and mesyl chloride, etc.) orwith an acid derivative (ethyl chloroformate and isobutyl chloroformateetc.) at 0 to 40° C. in the presence or absence of an organic solvent(chloroform, dichloromethane, diethyl ether, and tetrahydrofuran, etc.)or without a solvent in the presence of a base (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, and diisopropylethylamine, etc.)and the resulting mixed acid anhydride is subjected to a reaction withan amine in an organic solvent (chloroform, dichloromethane, diethylether, tetrahydrofuran, etc.) at 0 to 40° C. This reaction is preferablycarried out under anhydrous condition under inert gas atmosphere (argonand nitrogen etc.).

(3) A process using a condensing agent is carried out, for example, insuch a manner that carboxylic acid is subjected to a reaction with anamine, using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,1-propylphosphonic acid cyclic anhydride; PPA, etc., with or without1-hydroxybenztriazole (HOBt), in the presence or absence of a base(pyridine, triethylamine, dimethylanilin, dimethylaminopyridine, etc.)in an organic solvent (chloroform, dichloromethane, dimethylformamide,diethyl ether, tetrahydrofuran, etc.) or without a solvent. at 0 to 40°C. This reaction is preferably carried out under anhydrous conditionunder inert gas atmosphere (argon and nitrogen etc.).

The deprotection reaction of a protective group for carboxyl, hydroxyl,amino, or thiol is known and its examples are as follows;

-   (1) a hydrolyzing reaction with an alkali;-   (2) a deprotection reaction under an acidic condition;-   (3) a deprotection reaction by hydrogenolysis;-   (4) a deprotection reaction of silyl;-   (5) a deprotection reaction using metal; and-   (6) a deprotection reaction using an organic metal.

Those methods will be specifically illustrated as follows.

(1) A deprotection reaction using an alkali is carried out, for example,at the temperature of 0 to 40° C. using a hydroxide of alkaline metal(sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), ahydroxide of alkaline earth metal (barium hydroxide and calciumhydroxide etc.), a carbonate (sodium carbonate and potassium carbonateetc.), an aqueous solution thereof or a mixture thereof in an organicsolvent (methanol, tetrahydrofuran and dioxane etc.).

(2) A deprotection reaction under an acidic condition is carried out,for example, at the temperature of 0 to 100° C. in an organic acid(acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylicacid, etc.), an inorganic acid (hydrochloric acid and sulfuric acid,etc.) or a mixture thereof (hydrogen bromide/acetic acid etc) in anorganic solvent (dichloromethane, chloroform, dioxane, ethyl acetate,and anisole, etc.) in the presence or absence of 2,2,2-trifluoroethanol.

(3) A deprotection reaction by hydrogenolysis is carried out, forexample, at the temperature of 0 to 200° C., under hydrogen atmosphereof ordinary pressure or high pressure or in the presence of ammoniumformate, in the presence of a catalyst (palladium-carbon, palladiumblack, palladium hydroxide, platinum hydroxide, platinum oxide, andRaney nickel, etc.), in a solvent (ethers (tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol,etc.), benzenes (benzene, toluene, etc.), ketones (acetone, methyl ethylketone, etc.), nitrites (acetonitrile etc.), amides (dimethylformamideetc.), water, ethyl acetate, acetic acid, or a mixed solvent comprisingtwo or more thereof, etc.).

(4) A deprotection reaction of silyl is carried out, for example, at thetemperature of 0 to 40° C. using tetrabutylammonium fluoride in anorganic solvent miscible with water (tetrahydrofuran, acetonitrile,etc.).

(5) A deprotection reaction using metal is carried out, for example, atthe temperature of 0 to 40° C. with ultrasonic wave, if necessary, inthe presence of powdery zinc in an acidic solvent (acetic acid, a bufferof pH 4.2 to 7.2 and a mixed solution of a solution thereof and anorganic solvent such as tetrahydrofuran).

(6) A deprotection reaction using a metal complex is carried out, forexample, at the temperature of 0 to 40° C. using a metal complex(tetrakistriphenylphosphine palladium (0),bis(triphenylphosphine)palladium (II) dichloride, palladium (II)acetate, tris(triphenylphosphine) rhodium (I) chloride, etc.), in thepresence or absence of a phosphine agent (triphenyl phosphine etc.), inthe presence of a trap reagent (tributyltin hydride, triethylsilane,dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid(acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or an organicacid salt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.) inan organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran,ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixedsolvent thereof.

Besides the aforementioned, the deprotection is carried out by a methoddescribed in T. W. Greene, Protective Groups in Organic Synthesis,Wiley, N.Y., and 1999.

The protective group for carboxyl includes such as, e.g., methyl, ethyl,allyl, t-butyl, trichloroethyl group, benzyl (Bn), phenacyl,p-methoxybenzyl, trityl, 2-chlorotrityl, solid phase carrier thereof,etc.

The protective group for hydroxyl includes such as, e.g., methyl,trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl(MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl(TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS),acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl,allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), etc.

The protective group of amino includes such as, e.g., benzyloxycarbonyl,tert-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

The protective group for thiol includes such as, e.g., benzyl,methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP),diphenylmethyl, acetyl (Ac), etc.

With regard to the protective group for carboxyl, hydroxyl, amino, andthiol, there is no particular limitation to the above ones so far as itis a group which can be easily and selectively detached. For example,the one described in “T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, N.Y., 1999” can be used.

As a person skilled in the art can easily understand it, the aimedcompound of the present invention can be easily produced by usingappropriate ones among those deprotection reactions.

(b) A compound of formula (IA) in which E represents —CH₂—, i.e., acompound represented by formula (IA-2)

wherein all symbols have the same meanings as the aforementioned, can beproduced by subjecting a compound represented by formula (II-1) orformula (II-2) and a compound represented by formula (IV)

wherein all symbols have the same meanings as the aforementioned, to areductive amination reaction, followed by subjecting to deprotection, ifnecessary.

The reductive amination reaction has been known, for example, it iscarried out at the temperature of 0 to 40° C. in the presence of areducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride,sodium borohydride, etc.) in an organic solvent (tetrahydrofuran,diethyl ether, dichloroethane, dichloromethane, dimethylformamide,acetic acid, a mixture thereof, etc.) or at the temperature of 0 to 200°C. in the presence of a catalyst (palladium-carbon, palladium black,hydroxide palladium, oxidation platinum, Raney Nickel, etc.) in ansolvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethylether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene,toluene, etc.), ketones (acetone, methylethylketone, etc.), nitriles(acetonitrile etc.), amides (dimethyl formamide etc.), water, ethylacetate, acetate, or two or more mixed solvent thereof, etc.) underatmospheric or pressurized hydrogen atmosphere.

(c) A compound represented by formula (IA) also can be produced bysubjecting a compound represented by formula (V)

wherein all symbols have the same meanings as the aforementioned, and acompound represented by formula (VI)

wherein Z is a leaving group or hydroxyl and all other symbols have thesame meanings as the aforementioned, to an etherification reaction,followed by subjecting to deprotection, if necessary.

The etherification reaction has been known and is carried out, forexample, at 0° C. to a refluxing temperature in the presence of analkaline metal hydroxide (sodium hydroxide, potassium hydroxide, lithiumhydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide,calcium hydroxide, etc.), a carbonate (cesium carbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, etc.), an alkalinemetal hydride (sodium hydride, potassium hydride, etc.), potassiumphosphate (K₃PO₄), or an solution thereof, or a mixture thereof in anorganic solvent (dimethylformamide, dimethyl sulfoxide, chloroform,dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butylether, etc.) when the compound represented by formula (VI) in which Z isa leaving group is used. It is carried out, for example, at 0 to 60° C.in the presence of an azo compound (diethyl azodicarboxylate,diisopropyl azodicarboxylate, 1,1′-(azodicarbonyl)-dipiperidine,1,1′-azobis(N,N-dimethylformamide, etc.) and a phosphine compound(triphenyl phosphine, tributyl phosphine, trimethyl phosphine,polymer-supported triphenyl phosphine, etc.) in an organic solvent(dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene,toluene, etc.) when the compound represented by formula (VI) in which Zis hydroxyl is used.

(d) A compound in which R⁴ is R⁴⁻² or, i.e., a compound represented byformula (IA-3)

wherein all symbols have the same meanings as the aforementioned, alsocan to be produced by subjecting a compound represented by formula(IA-4)

wherein all symbols have the same meanings as the aforementioned to anN-alkylation reaction, followed by subjecting to deprotection, ifnecessary.

The N-alkylation reaction has been known and is carried out by thereaction of, for example, at 0 to 40° C. using an alkyl (C1-6) halide ora benzyl halide in the presence of a carbonate (cesium carbonate, sodiumcarbonate, potassium carbonate, etc.) in an organic solvent(dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane,diethyl ether, tetrahydrofuran, etc.).

In the case of a compound in which E in formula (IA-4) is —SO₂—, it alsois carried out, for example, at 0 to 60° C. using a C1-6 alkyl alcoholor benzyl alcohol in the presence of an azo compound (diethylazodicarboxylate, diisopropyl azodicarboxylate,1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide),etc.) and a phosphine compound (triphenyl phosphine, tributyl phosphine,trimethyl phosphoine, polymer-supported triphenyl phosphine, etc.) in anorganic solvent (dichloromethane, diethyl ether, tetrahydrofuran,acetonitrile, benzene, toluene, etc.).

II. A compound in which R¹ in formula (I) represents a hydrogen atom,i.e., a compound represented by formula (IB)

wherein all symbols have the same meanings as the aforementioned, can beproduced by subjecting a compound represented by formula (IA) to adeprotection reaction of a protective group for a carboxyl, followed bysubjecting to a deprotection reaction of a protective group forhydroxyl, amino, a nitrogen atom, or thiol, if necessary.

The deprotection reaction of carboxyl can be carried out by the samemethods as the aforementioned.

Though the persons skilled in the art can easily understand, the aimedcompound of the present invention can be easily prepared by using thesedeprotection reactions properly.

The deprotection reaction of hydroxyl, amino, a nitrogen atom, or thiolcan be carried out by the same methods as the aforementioned.

The compounds represented by formulae (II-1), (II-2), (III), (IV), (V),and (VI) have been known per se or can be easily produced by knownmethods.

For example, compounds in which Q¹ is methylene among the onesrepresented by formulae (II-1) and (II-2) can be produced by the processshown in the following reaction step formula 1.

In the reaction step formula 1, X represents a halogen atom, R⁴⁻³represents C1-5 alkyl or phenyl and other symbols have the same meaningsas the aforementioned.

Reaction Step Formula 1

For example, compounds in which Q¹ is —C(R^(12A))(R^(13A))—(R^(12A) andR^(13A) each independently represent C1-4 alkyl.) among the compoundsrepresented by formula (II-1) can be produced by the process shown inthe following reaction step formula 2.

In the reaction step formula 2, all symbols have the same meanings asthe aforementioned.

Reaction Step Formula 2

For example, compounds in which Q¹ is —C(R^(12A))(R^(13A))—(R^(12A) andR^(13A) together represent C2-5 alkylene (the said C2-5 alkylene may besubstituted by substituent(s).) in which the carbon atom may be replacedwith an oxygen atom, a nitrogen atom, or a sulfur atom that may beoxidized.)) among the compounds represented by formula (II-1) can beproduced by the process shown in the following reaction step formula2-1.

In the reaction step formula 2-1, Y represents C2-5 alkylene (the saidC2-5 alkylene may be substituted by substituent(s).) in which the carbonatom may replace an oxygen atom, a nitrogen atom, or a sulfur atom thatmay be oxidized and other symbols have the same meanings as theaforementioned.

Reaction Step Formula 2-1

For example, compounds in which Q1 is difluoromethylene or keto amongthe compounds represented by formula (II-1) can be produced by theprocess shown in the following reaction step formula 3.

In the reaction step formula 3, all symbols have the same meanings asthe aforementioned.

Reaction Step Formula 3

In the reaction step formula 1-3, the compounds represented by formulae(VII), (XII), and, (XV) used as starting materials have been known orcan be easily produced by known methods, e.g., the method described in“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc,1999)”.

Among the compounds of the present invention represented by formula (I),compounds expect for the above can be easily produced by a combinationof the methods described in examples in the present specification andknown methods, e.g., the methods described in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999)”.

As be well known by the persons skilled in the art, a reaction withheating in each reaction of the present specification may be carried outby using bathe, oil bath, sand bath, or microwave.

In each reaction of the present specification, solid-phase supportedreagents supported on high molecule polymer (e.g., polystyrene,polyacrylamide, polypropylene, polyethylene glycol, etc.) can beproperly used.

In each reaction described in the present specification, the reactionproduct can be purified by conventional purification techniques, e.g.,distillation under atmospheric or reduced pressure, high performanceliquid chromatography, thin-layer chromatography, or columnchromatography using silica gel or magnesium silicate, washing, orrecrystallization, etc. The purification may be carried out for eachreaction or after some reactions.

Application to Pharmaceuticals

Since the compounds of the present invention represented by formula (I)bind and antagonize to DP receptors, it is considered that the compoundsare useful for prevention and/or treatment of diseases mediated by DPreceptors such as allergic disease (e.g., allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy,etc.), systemic mastocytosis, disorders accompanied by systemic mastcell activation, anaphylaxis shock, bronchoconstriction, urticaria,eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis,migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome,contact dermatitis, diseases accompanied by itch (such as atopicdermatitis, urticaria, allergic conjunctivitis, allergic rhinitis andcontact dermatitis), diseases (e.g., cataract, retinal detachment,inflammation, infection, sleeping disorders, etc.) which are generatedsecondarily as a result of behavior accompanied by itch (scratching,beating, etc.), inflammation, chronic obstructive pulmonary diseases,ischemic reperfusion injury, cerebrovascular accident, autoimmunedisease, traumatic brain disorder, hepatopathy, graft rejection, chronicrheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease,ulcerative colitis, irritable bowel syndrome, interstitial cystitis,muscular dystrophy, polymyositis and multiple sclerosis. Further, thecompounds are considered to relate to sleeping and platelet aggregationand to be useful for these diseases.

Among the compounds of the present invention represented by formula (I),the compounds having a weak binding activity to receptors other than DPreceptors would be used as a pharmaceutical having less side effectsbecause it does not show other activity.

Toxicity

The toxicities of the compounds represented by formula (I) are very lowso that the compounds are sufficiently safe for using aspharmaceuticals.

The compounds of the present invention represented by formula (I),pharmaceutically acceptable salts thereof, and solvents thereof may beadministered as a combined preparation by combining with otherpharmaceuticals for the purpose of; (1) supplementing and/or enhancingof prevention and/or treatment effect of the compounds, (2) improvementin pharmacokinetics and absorption and reduction of dose of thecompounds and/or (3) reduction of side effects of the compounds.

The combined preparation with the compound of the present inventionrepresented by formula (I) and other pharmaceutical may be administeredin a form of a compounded agent in which both components are compoundedin a preparation or may be in a form in which they are administered bymeans of separate preparations. The case of administration by means ofseparate preparations includes a simultaneous administration andadministrations with time difference. In the case of administrationswith time difference, the compound of the present invention representedby formula (I) may be firstly administered followed by administering theother pharmaceutical or the other pharmaceutical may be administeredfirstly followed by administering the compound of the present inventionrepresented by formula (I). Methods for each of the administration arethe same or different.

The aforementioned other pharmaceuticals may be low molecular weightcompounds, proteins, polypeptides, polynucleotides (DNA, RNA, and gene),antisenses, decoys, antibodies, or vaccines, etc. The dosages of otherpharmaceuticals can be properly selected on the basis of the clinicaldose. Further, the compounding ratio of other pharmaceutical and thepharmaceutical of the present invention can be properly selected on thebasis of age and weight of a subject, medication method, administrationperiod, disease, symptom, combination, etc. For example, 0.01 to 100mass ratio of other pharmaceutical for 1 mass of the pharmaceutical ofthe present invention may be used. Two or more arbitrary otherpharmaceuticals may be combinationally administered at a suitable rate.Other pharmaceuticals supplementing and/or enhancing of preventionand/or treatment effect of the pharmaceutical of the present inventioninclude not only ones that were found up to the present, but also onesthat will be found in the future.

There is no particular limitation for the diseases showing preventionand/or treatment effect by the aforementioned combined preparation, sofar as it is a disease in which the prevention and/or treatment effectof the pharmaceutical of present invention are supplemented and/orenhanced.

Other pharmaceuticals for supplementing and/or enhancing the preventionand/or treatment effect of the compound of the present inventionrepresented by formula (I) for allergic rhinitis include, e.g.,antihistaminic agent, mediator release inhibitor, thromboxane synthetaseinhibitor, thromboxane A2 receptor antagonist, leukotriene receptorantagonist, steroid, α-adrenaline receptor stimulator, xanthinederivative, cholinergic-blocking agent, nitrogen monoxide synthaseinhibitor, etc.

Other pharmaceuticals for supplementing and/or enhancing the preventionand/or treatment effect of the compound of the present inventionrepresented by formula (I) for allergic conjunctivitis include, e.g.,leukotriene receptor antagonist, antihistaminic agent, mediator releaseinhibitor, non-steroid anti-inflammatory agent, prostaglandins, steroid,nitrogen monoxide synthase inhibitor, etc.

The antihistaminic agents include, e.g., ketotifen fumarate,mequitazine, azelastine hydrochloride, oxatomide, terfenadine,emedastine fumarate, epinastine hydrochloride, astemizole, ebastine,cetirizine hydrochloride, bepotastine, fexofenadine, loratadine,desloratadine, olopatadine hydrochloride, TAK427, ZCR-2060, NIP-530,mometasone furoate, mizolastine, BP-294, andrast, auranofin,acrivastine, etc.

The mediator release inhibitors include, e.g., tranilast, sodiumcromoglicate, amlexanox, repirinast, ibudilast, tazanolast, andpemirolast potassium etc. The thromboxane synthetase inhibitors include,e.g., ozagrel hydrochloride, imitrodast sodium, etc.

The thromboxane synthetase inhibitors include, e.g., ozagrelhydrochloride, imitrodast sodium.

The thromboxane A2 receptor antagonists include, e.g., seratrodast,ramatroban, domitroban calcium hydrate, KT-2-962, etc.

The leukotriene receptor antagonists include, e.g., pranlukast hydrate,montelukast, zafirlukast, MCC-847, KCA-757, CS-615, YM-158, L-740515,CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO4057, etc.

The steroid agents as its external application include, e.g., clobetasolpropionate, diflorasone acetate, fluocinonide, mometasonefurancarboxylate, betamethasone dipropionate, betamethasone butyratepropionate, betamethasone valerate, difluprednate, budesonide,diflucortolone valerate, amcinonide, halcinonide, dexamethasone,dexamethasone propionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate propionate,fluocinolone acetonide, beclomethasone propionate, triamcinoloneacetonide, flumethasone pivalate, alclometasone propionate, clobetasonevalerate, prednisolone, beclomethasone propionate, fludroxycortide, etc.

The internal medicines and injections include, e.g., cortisone acetate,hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, fludrocortisone acetate, prednisolone, prednisolone acetate,prednisolone sodium succinate, prednisolone butyl acetate, prednisolonesodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, betamethasone, etc.

The inhalation agents include, e.g., beclomethasone propionate,fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P,ciclesonide, dexamethasone palomithioate, mometasone furancarbonate,prasterone sulfonate, deflazacort, methylprednisolone suleptanate,methylprednisolone sodium succinate, etc.

The xanthine derivatives include, e.g., aminophylline, theophylline,doxophylline, cipamfylline, diprophylline, etc.

The anticholinergic agents include, e.g., ipratropium bromide,oxitropium bromide, flutropium bromide, cimetropium bromide, temiberin,tiotropium bromide, revatropate (UK-112166), etc.

The non-steroid anti-inflammatory agents include, e.g., sasapyrine,sodium salicylate, aspirin, aspirin dialuminate compounding, diflunisal,indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac,felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone,proglumetacin, indomethacin farnesyl, acemetacin, proglumetacin maleate,amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol,naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofencalcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium,aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate,tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone,piroxicam, tenoxicam, ampiroxicam, Napageln ointment, epirizole,tiaramide hydrochloride, tinoridine hydrochloride, emorfazone,sulpyrine, migrenin, salidon, Sedes G. Amipylo-N, Solbon,pyrazolone-type remedy for common cold, acetaminophen, phenacetin,dimethothiazine mesylate, simetride-compounded agent,non-pyrazolone-type remedy for common cold, etc.

There is no particular limitation for the ratio by weight of thecompound represented by formula (I) to other pharmaceutical.

Two or more of arbitrary other pharmaceuticals may be combinationallyadministered.

Other pharmaceuticals that supplement and/or enhance the preventionand/or treatment effect of the compound represented by formula (I)include not only one that has been already found but also one that willbe found in future on the basis of the aforementioned mechanism.

When the compounds represented by formula (I) or non-toxic salts thereofused in the present invention or combined preparations of the compoundrepresented by formula (I) and other pharmaceutical are used for theaforementioned purpose, they are systemically or topically administeredin an oral or parenteral form usually.

The dose varies depending upon age, body weight, symptom, therapeuticeffect, administering method, treating time and the like. Generally, 1mg to 1,000 mg per an adult is orally administered once to several timesper day, or 1 mg to 100 mg per an adult is parenterally administered(preferably, as a nasal agent, eye drops, or ointment) one to severaltimes per day, or is continuously administered from vein for 1 to 24hour(s) per day.

Since the dose changes depending on various conditions as describedabove, there are cases in which doses lower than or greater than theabove ranges may be used.

The compounds represented by formula (I) or non-toxic salts thereof or acombined preparation of the compound represented by formula (I) andother pharmaceutical is used as a solid composition, liquid composition,and other composition for oral administration or as injection, externalpreparation, suppository, etc., for parenteral administration.

The solid composition for oral administration includes tablets, pills,capsules, diluted powder, granules, etc.

The capsules include hard capsules and soft capsules.

In such a solid composition, one or more active substance(s) is mixedwith at least one inert diluent such as lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone and magnesium metasilicate aluminate. Thecomposition may contain an additive which is other than the inertdiluent by a conventional method such as a lubricant such as magnesiumstearate, a disintegrating agent such as calcium cellulose glycolate, astabilizer such as lactose and a solubilizing agent such as glutamicacid and aspartic acid. Tablet or pill may, if necessary, be coated withfilm of an intragastrically soluble or enteric substance such as sugar,gelatin, hydroxypropyl cellulose and hydroxypropyl methylcellulosephthalate or may be coated with two or more layers. Capsule of asubstance which can be absorbed such as gelatin is also included.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsion/suspension, solution, syrup, elixir, etc. In such aliquid composition, one or more active substance(s) is included in acommonly used inert diluent (such as pure water and ethanol). Thecomposition may contain an adjuvant such as moisturizer and suspendingagent, sweetener, flavor, aromatic agent and antiseptic agent besidesthe inert diluent.

Other composition for oral administration includes spray agent whichcontains one or more active substance(s) and is formulated by a knownmethod per se. Besides the inert diluent, the composition may contain astabilizer such as sodium hydrogen sulfite and a buffer givingisotonicity, e.g., isotonizing agent such as sodium chloride, sodiumcitrate, citric acid, etc. Method for the manufacture of spray agents isdescribed, e.g., in U.S. Pat. No. 2,868,691 and No. 3,095,355 in detail.

Parenteral injection of the present invention includes aseptic aqueousand/or non-aqueous solution, suspension, and emulsion. Aqueous solutionand suspension includes such as distilled water for injection andphysiological saline solution. Non-aqueous solution and suspensionincludes such as propylene glycol, polyethylene glycol, vegetable oilsuch as olive oil, alcohol such as ethanol and Polysorbate 80(Registered Trademark). It is also possible that aseptic and aqueous ornon-aqueous solution, suspension and emulsion may be mixed and used.Such a composition may further contain adjuvants such as antiseptic,moisturizer, emulsifier, dispersing agent, stabilizer (such as lactose)and solubilizing agent (such as glutamic acid and aspartic acid). Theyare sterilized by, e.g., filtration passing through a bacteria-fixingfilter, compounding of a disinfectant or irradiation. They may be alsoused in such a manner that, an aseptic solid composition is manufacturedand, before using as a freeze-dried product for example, they aredissolved in sterilized or aseptic distilled water for injection or inother solvents.

An administration form of eye drop for parenteral administrationincludes eye drops, eye drops of a suspension type, eye drops of anemulsion type, eye drops which is dissolved upon actual use, and eyeointment.

Such eye drops may be manufactured according to a known method. Forexample, in the case of the eye drops, an isotonizing agent (sodiumchloride, concentrated glycerol, etc.), a buffering agent (sodiumphosphate, sodium acetate, etc.), a surfactant (Polysorbate 80 (tradename), polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil,etc.), stabilizer (sodium citrate, sodium edentate, etc.), antisepticagent (benzalkonium chloride, paraben, etc.), and the like areappropriately selected and prepared upon necessity. They are sterilizedin the final step or prepared by an aseptic operation.

Inhalation agent for parenteral administration includes aerosolpreparation, powder for inhalation and liquid for inhalation. The liquidfor inhalation may be such a form that, the ingredient is dissolved orsuspended in water or in other appropriate medium in actual use.

Those inhalation agents are prepared according to a known method. Forexample, in the case of liquid for inhalation, antiseptic agent(benzalkonium chloride, paraben, etc.), coloring agent, buffer (sodiumphosphate, sodium acetate, etc.), isotonizing agent (sodium chloride,concentrated glycerol etc.), thickener (carboxyvinyl polymer, etc.),absorption promoter etc., are appropriately selected and prepared uponnecessity.

In the case of powder for inhalation, lubricant (stearic acid, saltthereof, etc.), binder (starch, dextrin, etc.), excipient lactose,cellulose, etc.), coloring agent, antiseptic (benzalkonium chloride,paraben, etc.), absorption promoter, etc., are appropriately selectedand prepared upon necessity.

In the administration of the liquid for inhalation, a spraying device(atomizer, nebulizer, etc.) are usually used and in the administrationof the powder for inhalation, an administering device for inhalation ofpowdery pharmaceutical is usually used.

Other compositions for parenteral administration include outer solution,ointment, liniment, and suppository for intrarectal administration, andpessary for intravaginal administration etc., containing one or moreactive compound(s) which can be prepared by known methods.

Benefits of the Invention

Since the compounds of the present invention represented by formula (I)bind and antagonize to DP receptors, it is considered that the compoundsare useful for prevention and/or treatment of diseases mediated by DPreceptor such as allergic disease (e.g., allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy,etc.), systemic mastocytosis, disorders accompanied by systemic mastcell activation, anaphylaxis shock, bronchoconstriction, urticaria,eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis,migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome,contact dermatitis, diseases accompanied by itch (such as atopicdermatitis, urticaria, allergic conjunctivitis, allergic rhinitis andcontact dermatitis), diseases (e.g., cataract, retinal detachment,inflammation, infection, sleeping disorders, etc.) which are generatedsecondarily as a result of behavior accompanied by itch (scratching,beating, etc.), inflammation, chronic obstructive pulmonary diseases,ischemic reperfusion injury, cerebrovascular accident, autoimmunedisease, traumatic brain disorder, hepatopathy, graft rejection, chronicrheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease,ulcerative colitis, irritable bowel syndrome, interstitial cystitis,muscular dystrophy, polymyositis and multiple sclerosis. Further thecompounds are considered to relate to sleeping and platelet aggregationand to be useful for these diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC. The solvents in the parentheses in NMR show thesolvents for measurement.

The compound names represented in examples were named by ACD/Name(Version 6.00, Advanced Chemistry Development Inc.).

Example 1 4-methoxy-2,3-dimethylbenzoic acid

4-methoxy-2,3-dimethylbenzaldehyde(14.8 g) was dissolved in a mixedsolvent of 2,2-dimethyl propanol (160 mL) and water (40 mL) and to themixture, sodium dihydrogenphosphate dihydrate (15.5 g),2-methyl-2-butene (43 mL), and sodium chlorite (28.5 g) weresequentially added, and the mixture was stirred for 2 hours at roomtemperature. Water and 1N hydrochloric acid were added to the reactionmixture, which was extracted with ethyl acetate. The organic layer waswashed with saturated brine solution and was dried by anhydrousmagnesium sulphate. The title compound (14.3 g) having the followingphysical data was obtained by allowing the residue obtained by removingthe solvent to recrystallize from a mixed solvent of n-hexane and ethylacetate.

TLC:Rf 0.52 (chloroform:methanol:acetate=9:1:0.1).

Example 2 4-hydroxy-2,3-dimethylbenzoic acid

Under argon atmosphere, to dichloromethane solution (50 mL) to which thecompound (14.3 g) prepared in Example 1 was dissolved, boron tribromidedichloromethane solution (1M, 160 mL) was added, which was stirredovernight at room temperature. To the reaction mixture, water is addedand the water layer of which the mixture was divided was extracted withethyl acetate. To the extract, the organic layer was mixed and themixture was washed with saturated brine solution and was dried byanhydrous magnesium sulphate. The title compound (13.2 g) having thefollowing physical data was obtained by allowing the residue obtained byremoving the solvent to recrystallize from the mixed solvent of n-hexaneand ethyl acetate.

TLC:Rf 0.32 (chloroform:methanol:acetate=9:1:0.1).

Example 3 methyl 4-hydroxy-2,3-dimethylbenzoate

Under argon atmosphere, to anhydrous methanol (20 mL) to whichthionylchloride (4.4 mL) was added at 0° C., a solution of the compound(5 g) prepared in Example 2 in anhydrous methanol (20 mL) was added. Thereaction mixture was stirred for 2 hours at 65° C. and was cooled downto room temperature, which was concentrated. The title compound (2.36 g)having the following physical data was obtained by purifying theobtained residue by silica gel column chromatography (n-hexane:ethylacetate=5:1).

TLC:Rf 0.29 (n-hexane:acetate=4:1).

Example 4 (2-fluorophenyl)methylamine

Under argon atmosphere, formate (6.1 mL) was dropped to acetic anhydride(15.5 mL) at 0° C., which was stirred for 2 hours at 50° C. After beingcooled down to room temperature, the reaction mixture was diluted withtetrahydrofuran (THF; 10 mL). To the diluent, a solution of2-fluoroaniline (5.56 g) in THF (20 mL) was added at room temperatureand the mixture was stirred for 1 hour at room temperature. The obtainedresidue by which the reaction mixture was concentrated was dissolved toanhydrous THF (25 mL). Under argon atmosphere, to the anhydrous THF (25mL) solution, borane tetrahydrofuran complex (1M THF solution; 125 mL)was added at 0° C. and the mixture was stirred for 2 hours at 50° C.After the reaction mixture was cooled down to room temperature, methanol(30 mL) and 4N hydrogen chloride dioxane solution (10 mL) were added onice bath and the mixture was stirred for 1 hour at 60° C. Theconcentrated reaction mixture was added to 2N sodium hydroxide solutionand was extracted with ethyl acetate. The organic layer was washed withsaturated brine solution and was dried by anhydrous sodium sulfate. Thesolution was filtered with celite (trade name) and the filtrate wasconcentrated. To the residue, the mixed solvent (hexane:ethylacetate=10:1 )was added and was filtered on silicagel. The titlecompound (6.45 g) was obtained by concentrating the effluent.

Example 5 (2S)-3-((2-fluorophenyl)(methyl)amino)-1,2-propanediol

Under argon atmosphere, a mixture of the compound (1.24 g) prepared inExample 4, (R)-(+)-glycidol (1.11 g, aldrich, 98% ee), and ethanol (1mL) was stirred for 12 hours at 50° C. The title compound having thefollowing physical data was obtained by concentrating the reactionmixture. The obtained title compound was used for the following reactionin no purification.

TLC:Rf 0.40 (n-hexane:ethyl acetate=1:1).

Example 6 ((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methanol

To a solution of the compound prepared in Example 5 in anhydrousdimethylformamide (DMF; 10 mL), potassium t-butoxide (1.68 g) was added,and the mixture was stirred for 3 hours at 80° C. The reaction mixturewas added to water, which was extracted with ethyl acetate. The organiclayer was washed with saturated brine solution and was dried byanhydrous sodium sulfate. The solution was filtered with celite (tradename) and was concentrated. The title compound (1.55 g, 97.6% ee) havingthe following physical data was obtained by purifying the residue withsilica gel column chromatography (hexane:ethyl acetate=3:1).

TLC:Rf 0.35 (n-hexane:ethyl acetate=2:1).

The optical purity of the title compound was decided by using highperformance liquid chromatography (HPLC).

Column: CHIRALCEL OD (Daicel Chemical Industries, Ltd.), 0.46 cmφ×25 cm

Flow rate: 1 mL/minute

Solvent:hexane: 2-propanol=93:7

Detection wave-length: 254 nm

Retention time: 30.70 minutes

Temperature: 24° C.

Example 7 ((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl4-methylbenzenesulfonate

Under argon atmosphere, to a solution of the compound (3.06 g) preparedin Example 6 in tetrahydrofuran (9 mL), triethylamine (5 mL) was added.To the reaction solution, a solution of p-toluenesulfonic acid chloride(3.42 g) in tetrahydrofuran (9 mL) and N,N-dimethylaminopyridine (209mg) were added and the mixture was stirred for 4 hours at roomtemperature. After adding water, the reaction solution was extracted bytert-butylmethyl ether. The extract was solidified by adding isopropylalcohol to the residue obtained by concentrating the organic layer. Thetitle compound (5.12 g) having the following physical data was obtainedby washing the filtered solid with isopropyl alcohol and drying.

TLC:Rf 0.81 (n-hexane:ethyl acetate=1:1).

Example 8 methyl2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoate

Under argon atmosphere, to anhydrous N,N-dimethylformamide (40 mL)solution to which the compound (2.05 g) prepared in Example 3 wasdissolved, cesium carbonate (7.82 g) and the compound (4.0 g) preparedin Example 7 was sequentially added. The reaction mixture was stirredfor 4 hours at 75° C. After being cooled down to room temperature, waterwas added to the reaction mixture, which was extracted with ethylacetate. The organic layer was washed with water and saturated brinesolution and was dried by anhydrous magnesium sulphate. The titlecompound (3.89 g) having the following physical data was obtained bypurifying the residue obtained by removing the solvent by silica gelcolumn chromatography (n-hexane:ethyl acetate=4:1).

TLC:Rf 0.73 (n-hexane:ethyl acetate=2:1).

Example 92,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoicacid

To the compound (3.85 g) prepared in Example 8, 1,2-dimethoxyethane (40mL), methanol (40 mL), and 1N sodium hydroxide solution (30 mL) wereadded. The reaction mixture was carbonized overnight at 67° C. Afterbeing cooled down to room temperature, methyl tert-butyl ether was addedto the reaction mixture. After being extracted by 1N sodium hydroxidesolution, the water layer was neutralized with 5N hydrochloric acid. Thewater layer was extracted with ethyl acetate and the organic layer waswashed with water and saturated brine solution and was dried byanhydrous magnesium sulphate. The title compound (3.70 g) having thefollowing physical data was obtained by allowing the residue obtained byremoving the solvent to recrystallize from the mixed solvent of n-hexaneand ethyl acetate.

TLC:Rf 0.24 (n-hexane:ethyl acetate=2:1).

Example 102,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride

Under argon atmosphere, the compound (400 mg) prepared in Example 9 wasdissolved to 1,2-dimethoxyethane (6.0 mL). AnhydrousN,N-dimethylformamide (one drop) and oxalyl chloride (0.22 mL) wereadded to the reaction mixture, which was stirred for 30 minutes at 40°C. The title compound was obtained by concentrating the reactionmixture.

Example 11 methyl(3-amino-4-fluorophenyl)acetate

A mixture of 4-fluoro-2-nitrobenzoic acid (23.1 g), oxalyl chloride (16mL), N,N-dimethylformamide (0.10 mL), and 1,2-dimethoxyethane (250 mL)was stirred for 1 hour at room temperature. The acid chloride wasobtained by concentrating the reaction mixture.

To a solution (2.0 M, 75 mL) of trimethylsilyldiazomethane in n-hexaneand a solution of triethylamine (35 mL) in tetrahydrofuran (100 mL), asolution of the previous acid chloride in tetrahydrofuran (250 mL) wasdropped and was stirred for 1 hour at room temperature. The reactionmixture was diluted with ethyl acetate and the extracted solid wasseparated. Water was added to the filtrate, which was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine solution and was dried by anhydrous magnesium sulphate. Thediazoketone was obtained by removing the solvent.

To a solution (250 mL) of the diazo ketone and triethylamine (15.7 mL)in ethanol, silver acetate (2.09 g) was added at room temperature, themixture was stirred during for 30 minutes at room temperature and for 30minutes at 66° C. In addition, silver acetate (2.09 g) was added and wasstirred for 30 minutes at 66° C. After being cooled down to roomtemperature, ethyl acetate and water were added to the reaction mixture,which was filtered with celite (trade name). The organic layer that wasseparated from the filtrate was washed with water and saturated brinesolution and was dried by anhydrous magnesium sulphate.

Ethyl ester (3.89 g) was obtained by purifying the residue obtained byremoving the solvent by silica gel column chromatography (n-hexane:ethylacetate=8:1). A solution (135 mL) of the ethyl ester and iron (18.8 g)in acetic acid was stirred for 1 hour half at 60° C. The reactionmixture was diluted with the toluene and was filtered with celite (tradename). The filtrate was washed with water and saturated brine solution,and was dried by anhydrous magnesium sulphate. The title compound (10.4g) having the following physical data was obtained by removing thesolvent.

TLC:Rf 0.69 (n-hexane:ethyl acetate=2:1).

Example 12methyl(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetate

To a solution (1.0 mL) of the compound (135 mg) prepared in Example 11in dichloromethane, pyridine (0.10 mL) and a solution (1.5 mL) of thecompound (210 mg) prepared in Example 10 in dichloromethane weresequentially added. The reaction mixture was stirred for 30 minutes atroom temperature. 1N hydrochloric acid (3.0 mL) and water were added tothe reaction mixture, which was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine solution and wasdried by anhydrous magnesium sulphate. The title compound (250 mg)having the following physical data was obtained by purifying the residueobtained by removing the solvent by silica gel column chromatography(n-hexane:ethyl acetate=3:1).

TLC:Rf 0.44 (n-hexane:ethyl acetate=2:1).

Example 13(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid

To a mixture of the compound (240 mg) prepared in Example 12,1,2-dimethoxyethane (5.0 mL), and methanol (5.0 mL), 1N sodium hydroxidesolution (3.0 mL) was added, and the mixture was stirred for 1 hour atroom temperature. Methyl tert-butylmethyl ether was added to thereaction mixture, which was extracted by 1N sodium hydroxide solution.The water layer was neutralized by adding 5N hydrochloric acid and wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine solution, and was dried by anhydrous magnesiumsulphate. The title compound (208 mg) having the following physical datawas obtained by allowing the residue obtained by removing the solvent torecrystallize from a mixed solvent of n-hexane, ethyl acetate, andtetrahydrofuran.

Property: crystal;

TLC:Rf 0.53 (chloroform:methanol:acetate=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.16, 2.29, 2.85, 3.22, 3.40, 3.57, 4.22, 4.60, 6.59,6.76, 6.94, 7.10, 7.19, 7.29, 7.57, 9.88, 12.35.

Example 13(1)-Example 13(31)

The compounds of the present invention having the following physicaldata were obtained by the same procedures as Example 12→Example 13 usinga corresponding acid chloride instead of the compound prepared inExample 10, or using a corresponding amine instead of the compoundprepared in Example 11.

Example 13(1)(4-chloro-3-(2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.40(n-hexane:ethyl acetate:acetic acid=50:50:1);

¹H-NMR:(CDCl₃) δ 2.23, 2.43, 2.92, 3.29, 3.42, 3.70, 4.16, 4.27, 4.67,6.69, 6.85, 7.02, 7.36, 7.94, 8.52.

Example 13(2)(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.54(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.38, 2.91, 3.24, 3.39, 3.72, 4.12, 4.24, 4.63, 6.69,6.86, 7.05, 7.37, 7.74, 8.50.

Example 13(3)(4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

TLC:Rf 0.54(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.84, 3.22, 3.39, 3.61, 4.41, 4.63, 6.59, 6.77, 7.16,7.37, 7.48, 7.71, 7.84, 9.82, 12.42.

Example 13(4)(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.29(chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.42, 2.85, 3.22, 3.38, 3.58, 4.22, 4.59, 6.58,6.70, 6.78, 6.87, 7.12, 7.38, 7.41, 7.54, 9.61, 12.36.

Example 13(5)(4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.49(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.85, 3.21, 3.41, 3.60, 4.30, 4.61, 6.60, 6.76,7.11, 7.47, 7.64, 7.81, 9.57.

Example 13(6)(4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.44(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.84, 3.17, 3.38, 3.61, 4.38, 4.62, 6.60, 6.76, 7.15,7.39, 7.48, 7.65, 7.74, 9.75, 12.42.

Example 13(7)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.43(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.16, 2.22, 2.32, 2.85, 3.22, 3.40, 3.52, 4.21, 4.60,6.59, 6.77, 6.99, 7.17, 7.30, 9.59, 12.28.

Example 13(8)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.55(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.15, 2.26, 2.84, 3.22, 3.40, 3.47, 4.21, 4.59, 6.59,6.76, 6.93, 7.23, 7.44, 10.08, 12.29.

Example 13(9)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.42(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.16, 2.26, 2.84, 3.22, 3.40, 3.52, 4.22, 4.59, 6.59,6.76, 6.95, 7.25, 7.56, 7.68, 10.15, 12.30.

Example 13(10)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.53(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.24, 2.83, 3.16, 3.35, 3.53, 4.18, 4.56, 6.59, 6.76,6.96, 7.25, 7.55, 7.67, 10.25, 12.31.

Example 13(11)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.33(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.24, 2.83, 3.16, 3.36, 3.47, 4.17, 4.55, 6.59, 6.75,7.43, 10.17, 12.28.

Example 13(12)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.55(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.23, 2.83, 3.16, 3.36, 3.58, 4.18, 4.55, 6.59, 6.75,7.13, 7.56, 7.72, 10.29.

Example 13(13)(5-(2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.36(n-hexane:ethyl acetate:acetic acid=50:50:1);

¹H-NMR:(DMSO-d₆) δ 2.17, 2.19, 2.35, 2.84, 3.21, 3.39, 3.52, 4.23, 4.59,6.59, 6.72, 6.79, 6.90, 7.09, 7.28, 7.47, 7.56, 9.99.

Example 13(14)(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.37(n-hexane:ethyl acetate:acetic acid=50:50:1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.36, 2.84, 3.21, 3.39, 3.57, 4.23, 4.59, 6.59,6.72, 6.79, 6.91, 7.12, 7.30, 7.58, 7.71, 10.12.

Example 13(15)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.60(chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.36, 2.84, 3.21, 3.39, 3.51, 4.23, 4.59, 6.59,6.72, 6.79, 6.94, 7.24, 7.29, 7.57, 7.66, 10.08.

Example 13(16)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.41(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.16, 2.26, 2.84, 3.22, 3.40, 3.59, 4.21, 4.59, 6.59,6.76, 6.94, 7.13, 7.25, 7.57, 7.73, 10.20, 12.46.

Example 13(17)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.50(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.15, 2.18, 2.26, 2.84, 3.21, 3.40, 3.52, 4.21, 4.59,6.59, 6.77, 6.93, 7.09, 7.23, 7.47, 7.57, 10.06.

Example 13(18)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.50(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.23, 2.83, 3.16, 3.36, 3.52, 4.17, 4.55, 6.59,6.76, 7.09, 7.46, 7.56, 10.14.

Example 13(19)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.46(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.24, 2.32, 2.84, 3.16, 3.36, 3.52, 4.18, 4.56, 6.59,6.76, 7.02, 7.17, 7.28, 9.71.

Example 13(20)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.43(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.28, 2.83, 3.16, 3.36, 3.56, 4.18, 4.56, 6.59, 6.76,7.14, 7.54, 10.02.

Example 13(21)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.47(chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 2.17, 2.38, 2.84, 3.21, 3.39, 3.56, 4.23, 4.59, 6.59,6.72, 6.79, 6.91, 7.09, 7.18, 7.35, 7.54, 9.81.

Example 13(22)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.62(chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.21, 2.40, 2.84, 3.21, 3.39, 3.51, 4.23, 4.59,6.60, 6.72, 6.79, 6.91, 7.01, 7.16, 7.25, 7.35, 9.55.

Example 13(23)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid

Property: crystal;

TLC:Rf 0.47(chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 2.17, 2.26, 2.35, 2.84, 3.21, 3.39, 3.46, 4.23, 4.59,6.61, 6.76, 6.91, 7.28, 7.43, 10.00.

Example 13(24)(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.46(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.39, 3.73, 4.21, 4.40, 4.57, 6.66, 6.88, 7.06, 7.37,7.73, 8.51.

Example 13(25)(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.46(chloroform:methanol:acetic acid=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 2.16, 2.26, 2.84, 3.22, 3.40, 3.67, 4.22, 4.59, 6.59,6.76, 6.95, 7.26, 7.37, 7.61, 7.80, 10.29, 12.46.

Example 13(26)(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.39(n-hexane:ethyl acetate:acetic acid=66:33:1);

¹H-NMR:(DMSO-d₆) δ 2.23, 2.83, 3.16, 3.36, 3.67, 4.18, 4.55, 6.59, 6.75,7.38, 7.60, 7,79, 10.39.

Example 13(27)(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.42(n-hexane:ethyl acetate:acetic acid=66:33:1);

¹H-NMR:(DMSO-d₆) δ 2.18, 2.36, 2.84, 3.21, 3.39, 3.66, 4.24, 4.59, 6.59,6.72, 6.79, 6.92, 7.31, 7.37, 7.61, 7.79, 10.21.

Example 13(28)(4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.39(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.38, 3.72, 3.92, 4.02, 4.16, 4.51, 4.71, 6.63, 6.84,6.89, 7.05, 7.18, 7.30, 7.37, 7.73, 8.51.

Example 13(29)(4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.39(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.30, 2.38, 3.73, 3.88, 3.99, 4.16, 4.50, 4.69, 6.63,6.73, 6.98, 7.05, 7.09, 7.37, 7.73, 8.52.

Example 13(30)(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid

Property: crystal;

TLC:Rf 0.40(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.38, 3.13, 3.40, 3.73, 4.10, 4.22, 5.15, 6.65, 6.85,7.05, 7.17, 7.37, 7.73, 8.51.

Example 13(31)(3-((4-(1,3-benzodioxol-2-ylmethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)aceticacid

Property: crystal;

TLC:Rf 0.39(chloroform:methanol=9:1);

¹H-NMR:(CDCl₃) δ 2.38, 3.72, 4.27, 6.44, 6.66, 6.85, 7.05, 7.37, 7.73,8.50.

Example 14 methyl 2-(4-chloro-3-nitrophenyl)propanoate

Under argon atmosphere, to a solution (14 mL) of methyl(4-chloro-3-nitrophenyl)acetate (300 mg) in tetrahydrofuran, methyliodide (0.26 mL), lithium N,N-diisopropyl amidocyclohexane solution(1.5M, 2.32 mL) were dropped at −78° C. The reaction mixture was stirredfor 2 hours with rising temperature up to room temperature. Water wasadded to the reaction mixture, which was extracted with ethyl acetate.The organic layer was sequentially washed with diluted hydrochloricacid, water, and saturated brine solution, and was dried by anhydrousmagnesium sulphate. The compound (245 mg) of the present inventionhaving the following physical data was obtained by purifying the residueobtained by removing the solvent by silica gel column chromatography(n-hexane:ethyl acetate=5:1).

TLC:Rf 0.37 (n-hexane:ethyl acetate=4:1).

Example 15 methyl 2-(4-chloro-3-nitrophenyl)-2-methylpropanoate

Under argon atmosphere, to a solution (5 mL) of the compound prepared inExample 14 in tetrahydrofuran, methyl iodide (0.01 mL) and lithiumN,N-diisopropyl amidocyclohexane solution (1.5M, 0.83 mL) were droppedat −78° C. The reaction mixture was stirred for 2 hours with risingtemperature up to room temperature. Water was added to the reactionmixture, which was extracted with ethyl acetate. The organic layer wassequentially washed with diluted hydrochloric acid, water, and saturatedbrine solution, and was dried by anhydrous magnesium sulphate. Thecompound (118 mg) of the present invention having the following physicaldata was obtained by purifying the residue obtained by removing thesolvent by silica gel column chromatography (n-hexane:ethylacetate=8:1).

TLC:Rf 0.42 (n-hexane:ethyl acetate=4:1).

Example 16 methyl 2-(3-amino-4-chlorophenyl)-2-methylpropanoate

The compound (116 mg) prepared in Example 15 was dissolved to a mixedsolvent of acetate (2.5 mL) and water (0.5 mL). Iron filings (133 mg)was added to the reaction mixture that was warmed up to 80° C., whichwas stirred for 30 minutes. Water was added to the reaction mixture,which was extracted with ethyl acetate. The organic layer wassequentially washed with saturated sodium hydrogencarbonate solution,water, and saturated brine solution, and was dried by anhydrousmagnesium sulphate. The compound (102 mg) of the present inventionhaving the following physical data was obtained by removing the solvent.

TLC:Rf 0.26 (n-hexane:ethyl acetate=4:1).

Example 172-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride

Under argon atmosphere, oxalylchloride (0.3 mL) andN,N-dimethylformamide (1 drop) were added to a solution (4.5 mL) of2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoicacid (488 mg: the compound produced by the same procedures as a seriesof Example 8→Example 9→Example 10 using methyl4-hydroxy-2-chlorobenzoate instead of the compound produced in Example3.) in 1,2-dimethoxyethane, which was stirred for 1 hour at 40° C. Thetitle compound was obtained by concentrating the reaction mixture.

Example 18 methyl2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate

A solution of the compound prepared in Example 17 in dichloromethane(1.8 mL) was dropped to a solution of the compound (100 mg) prepared inExample 16 in dichloromethane (1.8 mL). Pyridine (0.057 mL) was added tothe reaction mixture, which was stirred for 1 hour at room temperature.The reaction mixture dissolved to water was extracted with ethylacetate. The organic layer was sequentially washed with dilutedhydrochloric acid, saturated sodium hydrogencarbonate solution, andsaturated brine solution and was dried by anhydrous magnesium sulphate.The title compound (164 mg) having the following physical data wasobtained by purifying the residue obtained by removing the solvent bysilica gel column chromatography (n-hexane:ethyl acetate=4:1).

TLC:Rf0.41 (n-hexane:ethyl acetate=2:1).

Example 192-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoicacid

To a mixture of the compound (162 mg) prepared in Example 18,tetrahydrofuran (1.5 mL), and methanol (1.5 mL), 1N sodium hydroxidesolution (0.6 mL) was added, and the mixture was stirred for 4 hours at50° C. In addition, 2N sodium hydroxide solution (0.6 mL) was added toit, which was stirred for 3 hours at 50° C. The reaction mixture wasneutralized by adding 2N hydrochloric acid (0.6 mL) and was extractedwith ethyl acetate after adding water. The organic layer was washed withsaturated brine solution and was dried by anhydrous magnesium sulphate.The title compound (124 mg) having the following physical data wasobtained by purifying the residue obtained by removing the solvent bysilica gel column chromatography (methylene chloride:ethyl acetate=4:1).

Property: amorphous;

TLC:Rf 0.26 (n-hexane:ethyl acetate=1:1);

¹H-NMR:(CDCl₃) δ1.64, 2.91, 3.25, 3.38, 4.18, 4.27, 4.66, 6.71, 6.87,6.96, 7.04, 7.11, 7.36, 7.88, 8.71.

Example 20 (4-chloro-3-nitrophenyl)((trimethylsilyl)oxy)acetonitrile

To a mixture of 4-chloro-3-nitrobenzaldehyde (3.71 g), zinc iodide (128mg), and dichloromethane (50 mL), trimethylsilylcyanide (2.9 mL) wasadded at ice-cold temperature and the mixture was stirred for 1 hour atthe same temperature. 1N hydrochloric acid was added to the reactionmixture, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine solution and was dried byanhydrous magnesium sulphate. The title compound (5.95 g) having thefollowing physical data was obtained by removing the solvent.

TLC:Rf 0.55 (n-hexane:ethyl acetate=4:1).

Example 21 (4-chloro-3-nitrophenyl)(hydroxy)acetic acid

Concentrated hydrochloric acid (30 mL) was added to a solution of thecompound (5.95 g) prepared in Example 20 in acetate (30 mL), which wasstirred overnight at 90° C. The reaction mixture was soaked in ice afterbeing cooled and was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine solution and was dried byanhydrous magnesium sulphate. The title compound (4.48 g) having thefollowing physical data was obtained by removing the solvent.

TLC:Rf 0.14 (n-hexane:ethyl acetate=1:1).

Example 22 ethyl(4-chloro-3-nitrophenyl)(hydroxy)acetate

P-toluenesulfonic acid (367 mg) was added to a solution (50 mL) of thecompound (4.48 g) prepared in Example 21 in ethanol, which was stirredfor 4 hours at 70° C. The reaction mixture was cooled and was extractedwith ethyl acetate after adding water. The organic layer was washed withwater and saturated brine solution and was dried by anhydrous magnesiumsulphate. The title compound (4.83 g) having the following physical datawas obtained by removing the solvent.

TLC:Rf 0.37 (n-hexane:ethyl acetate=2:1).

Example 23 ethyl(4-chloro-3-nitrophenyl)(oxo)acetate

To a solution (10 mL) of the compound (1.59 g) prepared in Example 22 inacetic acid, 10% sodium hypochlorite solution (6.78 g) was added atice-cold temperature, and was stirred for 1 hour at the sametemperature. Acetate (10 mL) and 10% sodium hypochlorite solution (6.78g) were added to the reaction mixture, and further acetate (10 mL) and10% sodium hypochlorite solution (6.78 g) were added, and the mixturewas stirred for 2 hours. Water was added to the reaction mixture, whichwas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine solution and was dried by anhydrous magnesiumsulphate. The title compound (414 mg) having the following physical datawas obtained by purifying the residue obtained by removing the solventby silica gel column chromatography (n-hexane:ethyl acetate=4:1).

TLC:Rf 0.59 (n-hexane:ethyl acetate=2:1).

Example 24 ethyl(4-chloro-3-nitrophenyl)(difluoro)acetate

Under argon atmosphere, diethylaminosulfatrifluoride(DAST)(311 mg) wasadded to a solution (5 mL) of the compound (414 mg) prepared in Example23 in dichloromethane at ice-cold temperature, which was stirred for 2hours at room temperature and then for 2 hours at 45° C. Water was addedto the reaction mixture, which was extracted with ethyl acetate. Theorganic layer was sequentially washed with saturated sodiumhydrogencarbonate solution, water, and saturated brine solution and wasdried by anhydrous magnesium sulphate. The title compound (278 mg)having the following physical data was obtained by purifying by(n-hexane:ethyl acetate=9:7).

TLC:Rf 0.57 (n-hexane:ethyl acetate=4:1).

Example 25 ethyl(3-amino-4-chloro)(difluoro)acetate

The compound (253 mg) prepared in Example 24 was dissolved to the mixedsolvent of acetate (3 mL) and water (0.3 mL). Iron filings (253 mg) wasadded to the reaction mixture at 80° C., which was stirred for 30minutes at the same temperature. The reaction mixture was soaked in iceand was extracted with mixed solvent (1:1) of n-hexane and ethylacetate. The organic layer was washed with water and saturated brinesolution and was dried by anhydrous magnesium sulphate. The titlecompound (194 mg) having the following physical data was obtained byremoving the solvent.

TLC:Rf 0.48 (n-hexane:ethyl acetate=4:1).

Example 26ethyl(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetate

Under argon atmosphere, to a mixture of the compound (180 mg) preparedin Example 25, pyridine (0.5 mL), and dichloromethane (1 mL), a solution(4 mL) of the compound (303 mg) prepared in Example 17 indichloromethane was dropped at ice-cold temperature, and the mixture wasstirred overnight at room temperature. 1N hydrochloric acid was added tothe reaction mixture, which was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine solution and wasdried by anhydrous magnesium sulphate. The title compound (207 mg)having the following physical data was obtained by purifying the residueobtained by removing the solvent by silica gel column chromatography(n-hexane:ethyl acetate=4:1→3:1).

TLC:Rf 0.55 (n-hexane:ethyl acetate=2:1).

Example 27(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(difluoro)acetate

To a mixture of the compound (207 mg) prepared in Example 26, ethanol (4mL), and tetrahydrofuran (2 mL), 1N sodium hydroxide solution (1 mL) wasadded and the mixture was stirred for 2 hours at room temperature. Afterbeing neutralized by adding 1N hydrochloric acid, the reaction mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine solution and was dried by anhydrous magnesiumsulphate. The residue obtained by removing the solvent was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1→methylenechloride:methanol=9:1). The compound (135 mg) of the present inventionhaving the following physical data was obtained by washing the obtainedsolid by methyl tert-butyl ether.

Property: amorphous;

TLC:Rf 0.50 (dichloromethane:methanol:water=80:20:1);

¹H-NMR:(DMSO-d₆) δ 2.84, 3.17, 3.37, 4.28, 4.57, 6.59, 6.76, 7.09, 7.21,7.40, 7.58, 7.80, 10.12.

Example 28 ethyl(acetyloxy)(4-chloro-3-nitrophenyl)acetate

To a solution (6 mL) of the compound (1.46 g) prepared in Example 22 inpyridine, acetic anhydride (2 mL) was added, and the mixture was stirredfor 1 hour at room temperature. The title compound (135 mg) having thefollowing physical data was obtained by concentrating the reactionmixture and azeotroping in toluene.

TLC:Rf 0.56 (n-hexane:ethyl acetate=2:1).

Example 29 ethyl(acetyloxy)(3-amino-4-chlorophenyl)acetate

The compound (1.94 mg) prepared in Example 28 was dissolved to a mixedsolvent of acetate (10 mL) and water (1 mL). Iron filings (1.57 mg) wasadded to the reaction mixture at 80° C., which was stirred for 30minutes at the same temperature. The reaction mixture was soaked in iceand was extracted with a mixed solvent (1:1) of n-hexane and ethylacetate. The organic layer was washed with water and saturated brinesolution and was dried by anhydrous magnesium sulphate. The titlecompound (1.53 g) having the following physical data was obtained byremoving the solvent.

TLC:Rf 0.47 (n-hexane:ethyl acetate=4:1).

Example 30ethyl(acetyloxy)(4chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetate

Under argon atmosphere, to a mixture of the compound (196 mg) preparedin Example 29, pyridine (0.5 mL), and dichloromethane (1 mL), a solution(4 mL) of the compound (303 mg) prepared in Example 17 indichloromethane was dropped at ice-cold temperature, and the mixture wasstirred overnight at room temperature. 1N hydrochloric acid was added tothe reaction mixture, which was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine solution and wasdried by anhydrous magnesium sulphate. The title compound (207 mg)having the following physical data was obtained by purifying the residueobtained by removing the solvent by silica gel column chromatography(n-hexane:ethyl acetate=4:1→2:1).

TLC:Rf 0.39 (n-hexane:ethyl acetate=2:1).

Example 31ethyl(4chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(hydroxy)acetate

To a solution in which the compound (207 mg) prepared in Example 30 wasdissolved to a mixed solvent of ethanol and tetrahydrofuran (6 mL and2:1), potassium carbonate (138 mg) was added, and the mixture wasstirred for 2 hours at 50° C. Water was added to the cooled reactionmixture, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine solution and was dried byanhydrous magnesium sulphate. The title compound (169 mg) having thefollowing physical data was obtained by removing the solvent.

TLC:Rf 0.38 (n-hexane:ethyl acetate=1:1).

Example 32ethyl(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetate

Under argon atmosphere, to a mixture of the compound (159 mg) preparedin Example 31, diisopropylethylamine (0.30 mL), dimethylsulfoxide (2mL), and ethyl acetate (4 mL), sulfur trioxide pyridine complex (139 mg)were added at ice-cold temperature, and the mixture was stirred for 1hour at the same temperature. Water was added to the reaction mixture,which was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine solution and was dried by anhydrousmagnesium sulphate. The title compound (104 mg) having the followingphysical data was obtained by purifying the residue obtained by removingthe solvent by silica gel column chromatography (n-hexane:ethylacetate=3:1→2:1).

Example 33ethyl(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)aceticacid

To a mixture of the compound (104 mg) prepared in Example 32, ethanol (2mL), and tetrahydrofuran (2 mL), 1N sodium hydroxide solution (0.5 mL)was added and the mixture was stirred for 2 hours at room temperature.After being neutralized by adding 1N hydrochloric acid, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine solution and was dried by anhydrousmagnesium sulphate. The compound (37 mg) of the present invention havingthe following physical data was obtained by purifying the residueobtained by removing the solvent by silica gel column chromatography(n-hexane:ethyl acetate=2:1→methylene chloride:methanol=9:1).

Property: amorphous;

TLC:Rf 0.45 (dichloromethane:methanol:water=80:20:1);

¹H-NMR:(DMSO-d₆) δ 2.84, 3.17, 3.37, 4.30, 4.58, 6.60, 6.76, 7.09, 7.21,7.67, 8.10, 10.19.

Example 342-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoicacid

By the same procedures as a series of Example 18 and Example 19 usingthe compound (121 mg) prepared in Example 16 and2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(211 mg) (the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl4-hydroxy-2,6-dimethylbenzoate.), the title compound (132 mg) having thefollowing physical data was obtained.

Property: crystal;

TLC:Rf0.17 (hexane:ethyl acetate=2:1);

¹H-NMR:(DMSO-d₆) δ 1.47, 2.32, 2.84, 3.16, 3.36, 4.18, 4.55, 6.59, 6.75,7.24, 7.48, 7.55, 9.94.

Example 34(1)2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoicacid

By the same procedures as a series of Example 18 and Example 19 usingthe compound (139 mg) prepared in Example 16 and2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(211 mg) (the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl4-hydroxy-2,5-dimethylbenzoate.), the title compound (211 mg) having thefollowing physical data was obtained.

Property: amorphous;

TLC:Rf 0.18 (hexane:ethyl acetate=2:1);

¹H-NMR:(DMSO-d₆) δ 1.47, 2.18, 2.42, 2.84, 3.21, 3.39, 4.24, 4.60, 6.59,6.72, 6,79, 6.91, 7,22, 7.41, 7.47, 7.57, 9.69.

Example 352-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-methylphenyl)-2-methylpropanoicacid

By the same procedures as a series of Example 18 and Example 19 usingmethyl 2-(3-amino-4-methylphenyl)-2-methylpropanoate (132 mg)(thecompound prepared by the same procedures as Example 16) and2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(210 mg)(the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl4-hydroxy-2,5-dimethylbenzoate.), the title compound (202 mg) having thefollowing physical data was obtained.

Property: crystal;

TLC:Rf 0.43 (chloroform:methanol:ethyl acetate=9:1:0.1);

¹H-NMR:(DMSO-d₆) δ 1.45, 2.18, 2.20, 2.40, 2.84, 3.21, 3.39, 4.23, 4.59,6.60, 6.75, 6.91, 7.10, 7.19, 7.32, 7.37, 9.56, 12.29.

Example 36 methyl 2-(4-chloro-3-nitrophenyl)cyclopropanoate

To a solution of methyl 2-(4-chloro-3-nitrophenyl)acetate (2.0 g) anddibromoethane (3.8 mL) in N-methyl-2-pyrolidone(58 mL), sodium hydride(766 mg) was added at room temperature. Then, the mixture was stirredfor 1 hour at room temperature, for 1 hour at 40° C., and then for 1hour at 60° C. Further, sodium hydride (766 mg) was added to it, whichwas stirred for 20 minutes. 1N hydrochloric acid was added to thereaction solution at ice-cold temperature, which was extracted withhexane-ethyl acetate (1:1). The extract was dried by anhydrous magnesiumsulphate after being washed with saturated brine solution. The titlecompound (762 mg) having the following physical data was obtained byfiltering, concentrating, and purifying by silica gel columnchromatography (n-hexane:ethyl acetate=6:1).

TLC:Rf 0.62 (n-hexane:ethyl acetate=2:1).

Example 37 methyl 2-(4-chloro-3-aminophenyl)cyclopropanoate

The title compound (769 mg) having the following physical data wasobtained by the same procedures as Example 16 using the compound (899mg) prepared in Example 36.

TLC:Rf 0.58 (n-hexane:ethyl acetate=2:1).

Example 381-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylicacid

By the same procedures as a series of Example 18 and Example 19 usingthe compound (138 mg) prepared in Example 37 and2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(211 mg) (the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl4-hydroxy-2,6-dimethylbenzoate.), the title compound (79 mg) having thefollowing physical data was obtained.

Property: crystal;

TLC:Rf 0.59 (chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 1.13, 1.47, 2.32, 2.84, 3.16, 3.36, 4.18, 4.56, 6.59,6.76, 7.21, 7.43, 7.54, 9.93.

Example 38(1)1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylicacid

By the same procedures as a series of reactions of Example 18 andExample 19 using the compound (138 mg) prepared in Example 37 and2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(211 mg) (the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl4-hydroxy-2,5-dimethylbenzoate.), the title compound (79 mg) having thefollowing physical data was obtained.

Property: amorphous;

TLC:Rf 0.59 (chloroform:methanol=9:1);

¹H-NMR:(DMSO-d₆) δ 1.13, 1.46, 2.18, 2.42, 2.84, 3.21, 3.39, 4.24, 4.60,6.59, 6.72, 6.79, 6.91, 7.20, 7.42, 7.56, 9.67.

Example 38(2)1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarboxylicacid

By the same procedures as a series of reactions of Example 18 andExample 19 using the compound (207 mg) prepared in Example 37 and2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride(211 mg) (the compound prepared by the same procedures as a series ofExample 8→Example 9→Example 10 using methyl 4-hydroxy-2-ethylbenzoate.),the title compound (330 mg) having the following physical data wasobtained.

Property: amorphous;

TLC:Rf 0.60 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃) δ 1.27, 1.34, 1.71, 2.93, 2.93, 3.28, 3.42, 4.17, 4.29,4.67, 6.73, 6.86, 7.10, 7.34, 7.49, 7.94, 8.56.

Example 39 Ligand Binding Using Cells Expressing the Prostanoid DPReceptor

Chinese hamster ovary (CHO) cells expressing the human DP receptor werecultivated and, according to a common method, membrane fraction wasprepared. The membrane fraction (50 μL) (protein content: 42.65 μg), 100μL of an assay buffer (25 mmol/L HEPES-NaOH containing 1 mmol/L EDTA, 5mmol/L Mg²⁺ and 10 mmol/L Mn²⁺; pH7.4), 1 μL of a vehicle (dimethylsulfoxide; DMSO) or the compound of the present invention (finalconcentration of DMSO: 0.5%) and 50 μL of 10 nmol/L [³H]-PGD₂ (finalconcentration: 2.5 nmol/L) were added to a polyethylene tube, and anincubation mixture was incubated at the room temperature. In anon-specific binding group, 2 mmol/L PGD₂ was added instead of thevehicle (final concentration of PGD₂: 10 μmol/L). Twenty minutes later,1 mL of ice-cold wash buffer (10 mmol/L Tris-HCl buffer containing 0.01%bovine serum albumin (BSA) and 100 mmol/L NaCl; pH7.4) was added to thetube to terminate the reaction. Immediately, the membrane fraction wascollected on a glass fiber filter (GF/B) by filtration under reducedpressure. The membrane fraction on the glass fiber filter was washedonce with approximately 2 mL of wash buffer and the glass fiber filterwas dried. The dried glass fiber filter was place in a glass vial, aliquid scintillation cocktail was added thereto and radioactivity wasmeasured by a liquid scintillation counter.

A specific binding of [³H]-PGD₂ to the DP receptor was calculated bysubtracting the radioactivity in the non-specific binding group fromthose in the groups other than the non-specific binding group. Aninhibition by the compound of the present invention was calculated baseon the specific binding of [³H]-PGD₂ in the vehicle and the presentinvention groups. The Ki value (dissociation constant of the compound ofthe present invention) was calculated according to the following formulausing the estimated IC₅₀ value (concentration of the compound of thepresent invention required to inhibit the specific binding in thevehicle group by 50%).

Ki=IC50/(1+([L]*/Kd))

[L]*: Concentration of [³H]-PGD₂ (2.5 nmol/L)

Kd: Dissociation constant of [³H]-PGD₂

The Kd value of [³H]-PGD₂ was estimated from a non-linear regressionanalysis after calculating the specific bindings of [³H]-PGD₂ uponaddition of various concentrations of [³H]-PGD₂ in accordance with theabove-mentioned method.

From the results of the above measurement, it was found that thecompounds of the present invention strongly bound to the DP receptor atthe Ki values of not more than 10 μmol/L.

Example 40 Measurement of Antagonistic Activity Against the DP ReceptorUsing Cells Expressing the Prostanoid DP Receptor

CHO cells stably expressing the human DP receptor was constructed;seeded on a 24-well culture plate at a cell density of 1×10⁵ cells/welland incubated at 37° C. for 2 days in 5% CO₂. Each well was washed with500 μL of MEM (minimum essential medium) and the cells were incubated at37° C. for 10 minutes after adding 500 μL of MEM containing 2 μmol/L ofdiclofenac. After removal of the supernatant by aspiration, 450 μL of anMEM containing 1 mmol/L 3-isobutyl-1-methylxanthine, 2 μμmol/Ldiclofenac and 1% BSA (assay medium) was added, followed by incubationat 37° C. for 10 minutes. Reaction was initiated by addition of 50 μL ofan assay medium containing PGD₂ and vehicle or an assay mediumcontaining PGD₂ and the compound of the present invention (finalconcentration of PGD₂: 10 nmol/L), followed by incubation at 37° C. Tenminutes later, 500 μL of ice-cold trichloroacetic acid (TCA, 10% w/v)was added to terminate the reaction. After freezing (−80° C.) andthawing the reaction mixture once, the cells were detached therefromusing a cell scraper followed by centrifugation at 13,000 rpm for 3minutes. The resultant supernatant was collected and cAMP concentrationin the supernatant was determined by a radioimmunoassay using a cAMPassay kit (manufactured by Amersham). Thus, a buffer from the [¹²⁵I]cAMPassay kit was added to a 125 μL aliquot of the above-preparedsupernatant to be the volume of 500 μL and the resultant solution wasmixed with 1 mL of 0.5 mol/L tri-n-octylamine in chloroform. Afterextraction of TCA into a chloroform layer, the amount of cAMP in anaqueous layer was quantified according to the procedure mentioned in the[¹²⁵I]cAMP assay kit.

Potency of the antagonistic activity of the compound of the presentinvention for the DP receptor was expressed was calculated as IC₅₀ value(a concentration of the compound of the present invention which isnecessary to suppress the cAMP production in the absence of the compoundof the present invention by 50%) from inhibitory percentage to the cAMPproduction at 10 nmol/L, wherein PGD₂ elicited a submaximum cAMPproduction.

From the above-mentioned measuring results, it was found that thecompounds of the present invention strongly antagonized the DP receptorat the IC₅₀ values of not more than 10 μmol/L.

Formulation Example 1

The following components were admixed in conventional method and werepunched out to obtain 10,000 tablets each containing 10 mg of activeingredient.

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4- 100 gbenzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic acidCarboxymethyl Cellulose calcium(Disintegrator)  20 g Magnesiumstearate(Lubricant)  10 g Microcrystalline cellulose 870 g

Formulation Example 2

The following components were admixed in a conventional method, in whichthe mixture was filtered with dust removal filter and was placed at 5 mlinto ampoules. The ampoules were heat-sterilized by autoclave to therebyobtain 10,000 ampoules each containing 20 mg of the active ingredient.

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4- 200 gbenzoxazin-2-yl)methoxy)benzoyl)amino)-4-fluorophenyl)acetic acidMannitol  20 g Distilled water  50 L

INDUSTRIAL APPLICABILITY

Since the compounds of the present invention represented by formula (I)bind and antagonize to DP receptors, it is considered that the compoundsare useful for prevention and/or treatment of diseases mediated by DPreceptors such as allergic disease (e.g., allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma, food allergy,etc.), systemic mastocytosis, disorders accompanied by systemic mastcell activation, anaphylaxis shock, bronchoconstriction, urticaria,eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis,migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome,contact dermatitis, diseases accompanied by itch (such as atopicdermatitis, urticaria, allergic conjunctivitis, allergic rhinitis andcontact dermatitis), diseases (e.g., cataract, retinal detachment,inflammation, infection, sleeping disorders, etc.) which are generatedsecondarily as a result of behavior accompanied by itch (scratching,beating, etc.), inflammation, chronic obstructive pulmonary diseases,ischemic reperfusion injury, cerebrovascular accident, autoimmunedisease, traumatic brain disorder, hepatopathy, graft rejection, chronicrheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease,ulcerative colitis and irritable bowel syndrome. Further the compoundsare considered to relate to sleeping and platelet aggregation and to beuseful for these diseases.

1.-11. (canceled)
 12. A pharmaceutical composition comprising a compoundrepresented by formula (I)

wherein R¹ represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C2-4alkenyl, or (4) benzyl; E represents —CO—, —SO₂—, or —CH₂—; R²represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4)hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9)nitro, (10) —NR⁶R⁷, or (11) C1-4 alkyl substituted with —OR⁸, (12)oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15) —SR¹¹, or twoR²'s substituting for the adjacent carbon atom are taken together torepresent (1) C2-5 alkylene which may be substituted by a substituentwherein one carbon atom thereof may be replaced with an oxygen atom, anitrogen atom, or a sulfur atom which may be oxidized, or (2) C2-5alkenylene which may be substituted by a substituent, wherein one carbonatom thereof may be replaced with an oxygen atom, a nitrogen atom, or asulfur atom; R³ represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8)pyridyl, (9) nitro, (10) —NR⁶R⁷ or (11) C1-4 alkyl substituted with—OR⁸, (12) oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15)—SR¹¹; R⁶ and R⁷ each independently represent a hydrogen atom or C1-4alkyl; R⁸ represents C1-4 alkyl phenyl, or pyridyl; R⁴ represents (1) ahydrogen atom, (2) C1-6 alkyl, (3) benzyl, or (4) oxidized C1-6 alkyl;R⁵ represents (1) C1-6 alkyl, (2) C1-10 alkoxy, (3) C1-6 alkylsubstituted with C1-6 alkoxy, (4) a halogen atom, (5) hydroxyl, (6)trihalomethyl, (7) nitro, (8) —NR⁹R¹⁰, (9) phenyl, (10) phenoxy, (11)oxo, (12) C2-6 acyl, (13) cyano or (14) —SO₂R¹¹, (15) —SOR¹¹, (16)—SR¹¹, (12) oxidized C1-6 alkyl, R⁹ and R¹⁰ each independently representa hydrogen atom or C1-4 alkyl; and R¹¹ represents C1-6 alkyl or phenylwhich may be substituted; wherein R⁶'s to R¹¹'s in R²'s to R⁵'s may bethe same or each independently different; {circle around (w)} representsa C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to 12-memberedmonocyclic or bicyclic heterocycle; G represents (1) C1-6 alkylenehaving 0 to 2 hetero atoms selected from a nitrogen atom, an oxygenatom, and a sulfur atom, (2) C2-6 alkenylene having 0 to 2 hetero atomsselected from a nitrogen atom, an oxygen atom, and a sulfur atom, or (3)C2-6 alkynylene having 0 to 2 hetero atoms selected from a nitrogenatom, an oxygen atom, and a sulfur atom: {circle around (J)} representsa C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to 12-memberedmonocyclic or bicyclic heterocycle: m represents 0 or an integer of 1 to4, n represents 0 or an integer of 1 to 4, and i represents 0 or aninteger of 1 to 11, wherein R²'s may be the same or different when m is2 or more, R³'s may be the same or different when n is 2 or more, andR⁵'s may be the same or different when i is 2 or more: and R¹² and R¹³each independently represent (1) C1-4 alkyl which may be oxidized, (2) ahalogen atom, (3) trihalomethyl, (4) hydroxyl which may be protected,(5) amino which may be protected, (6) phenyl which may be substituted,(7) pyridyl which may be substituted, or (8) a hydrogen atom, or R¹² andR¹³ are taken together to represent (1) oxo, (2) C2-5 alkylene which maybe substituted by a substituent, wherein one carbon atom thereof may bereplaced with an oxygen atom, a nitrogen atom, or a sulfur atom, or (3)C1-6 alkylidene which may be substituted, and wherein when R¹² and R¹³each simultaneously represent a hydrogen atom, the carboxylic acidcompound represented by formula (I) represents a compound selected fromthe group consisting of the following compounds (1)-(32): (1)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid, (2)(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (3)(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (4)(4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (5)(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (6)(4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (7)(4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (8)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid, (9)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid, (10)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (11)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid (12)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid (13)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid (14)(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid, (15)(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid, (16)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (17)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid, (18)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid, (19)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid (20)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid (21)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid, (22)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3.4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid, (23)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid, (24)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid, (25)(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid, (26)(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (27)(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid. (28)(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (29)(4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid. (30)(4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (31)(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-1lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid, and (32)(3-((4-(1,3-benzodioxol-2-lymethoxy)-2,6-dimethylbenzoylamino)-4-chlorophenyl)aceticacid, a salt thereof, a solvate thereof, or a prodrug thereof, which isan agent for prevention and/or treatment of diseases mediated by DPreceptor.
 13. The pharmaceutical composition according to claim 12,wherein the disease mediated by DP receptor is allergic disease,systemic mastocytosis, disorders accompanied by systemic mast cellactivation, anaphylaxis shock, bronchoconstriction, urticaria, eczema,acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine,nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contactdermatitis, diseases accompanied by itch, diseases generated secondarilyas a result of behavior accompanied by itch, inflammation, chronicobstructive pulmonary diseases, ischemic reperfusion injury,cerebrovascular accident, autoimmune disease, traumatic brain disorder,hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy,osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowelsyndrome, interstitial cystitis, muscular dystrophy, polymyositis,multiple sclerosis, sleeping disorders or disease related to plateletaggregation.
 14. The pharmaceutical composition according to claim 13,wherein the allergic disease is allergic rhinitis, allergicconjunctivitis, atopic dermatitis, bronchial asthma or food allergy. 15.A pharmaceutical composition comprising a combination of the compoundrepresented by formula (I) according to claim 1, a salt thereof, asolvate thereof, or a prodrug thereof; and one or more kinds selectedfrom antihistaminic agent, suppressor for mediator liberation,thromboxane synthetase inhibitor, antagonist for thromboxane A2receptor, antagonist for leukotriene receptor, steroid agent,alpha-adrenergic receptor stimulator, xanthine derivative,anticholinergic agent, and nitric oxide synthase inhibitor. 16.-17.(canceled)
 18. A method for prevention and/or treatment of diseasesmediated by DP receptor, which comprises administering to a mammal aneffective amount of the compound represented by formula (I)

wherein R¹ represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C2-4alkenyl, or (4) benzyl: E represents —CO—, —SO₂—, or —CH₂—; R²represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4)hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9)nitro, (10) —NR⁶R⁷, or (11) C1-4 alkyl substituted with —OR⁸, (12)oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15) —SR¹¹, or twoR²'s substituting for the adjacent carbon atom are taken together torepresent (1) C2-5 alkylene which may be substituted by a substituentwherein one carbon atom thereof may be replaced with an oxygen atom, anitrogen atom, or a sulfur atom which may be oxidized, or (2) C2-5alkenylene which may be substituted by a substituent, wherein one carbonatom thereof may be replaced with an oxygen atom, a nitrogen atom, or asulfur atom; R³ represents (1) a halogen atom, (2) C1-6 alkyl, (3) C1-6alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8)pyridyl, (9) nitro, (10) —NR⁶R⁷ or (11) C1-4 alkyl substituted with—OR⁸, (12) oxidized C1-6 alkyl, (13) —SO₂R¹¹, (14) —SOR¹¹, or (15)—SR¹¹; R⁶ and R⁷ each independently represent a hydrogen atom or C1-4alkyl; R⁸ represents C1-4 alkyl, phenyl, or pyridyl; R⁴ represents (1) ahydrogen atom, (2) C1-6 alkyl, (3) benzyl, or (4) oxidized C1-6 alkyl;R⁵ represents (1) C1-6 alkyl, (2) C1-10 alkoxy, (3) C1-6 alkylsubstituted with C1-6 alkoxy, (4) a halogen atom, (5) hydroxyl, (6)trihalomethyl, (7) nitro, (8) —NR⁹R¹⁰, (9) phenyl, (10) phenoxy, (11)oxo, (12) C2-6 acyl, (13) cyano or (14) —SO₂R¹¹, (15) —SOR¹¹, (16)—SR¹¹, (12) oxidized C1-6 alkyl; R⁹ and R¹⁰ each independently representa hydrogen atom or C1-4 alkyl; and R¹¹ represents C1-6 alkyl or phenylwhich may be substituted; wherein R⁶'s to R¹¹'s in R²'s to R⁵'s may bethe same or each independently different; {circle around (W)} representsa C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to 12-memberedmonocyclic or bicyclic heterocycle; G represents (1) C1-6 alkylenehaving 0 to 2 hetero atoms selected from a nitrogen atom, an oxygenatom, and a sulfur atom, (2) C2-6 alkenylene having 0 to 2 hetero atomsselected from a nitrogen atom, an oxygen atom, and a sulfur atom, or (3)C2-6 alkynylene having 0 to 2 hetero atoms selected from a nitrogenatom, an oxygen atom, and a sulfur atom: {circle around (J)} representsa C5-12 monocyclic or bicyclic carbocyclic ring or a 5- to 12-memberedmonocyclic or bicyclic heterocycle: m represents 0 or an integer of 1 to4, n represents 0 or an integer of 1 to 4, and i represents 0 or aninteger of 1 to 11, wherein R²'s may be the same or different when m is2 or more, R³'s may be the same or different when n is 2 or more, andR⁵'s may be the same or different when i is 2 or more; and R¹² and R¹³each independently represent (1) C1-4 alkyl which may be oxidized, (2) ahalogen atom, (3) trihalomethyl, (4) hydroxyl which may be protected,(5) amino which may be protected, (6) phenyl which may be substituted,(7) pyridyl which may be substituted, or (8) a hydrogen atom, or R¹² andR¹³ are taken together to represent (1) oxo, (2) C2-5 alkylene which maybe substituted by a substituent, wherein one carbon atom thereof may bereplaced with an oxygen atom, a nitrogen atom, or a sulfur atom, or (3)C1-6 alkylidene which may be substituted, and wherein when R¹² and R¹³each simultaneously represent a hydrogen atom, the carboxylic acidcompound represented by formula (I) represents a compound selected fromthe group consisting of the following compounds (1)-(32); (1)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid, (2)(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (3)(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (4)(4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (5)(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (6)(4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (7)(4-chloro-3-((2,5-difluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (8)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid (9)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid (10)(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (11)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (12)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid, (13)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid, (14)(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid (15)(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid, (16)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (17)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-fluorophenyl)aceticacid, (18)(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid (19)(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-2-methylphenyl)aceticacid (20)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid, (21)(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid (22)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-fluorophenyl)aceticacid (23)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-4-methylphenyl)aceticacid, (24)(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)-5-methylphenyl)aceticacid, (25)(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid, (26)(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (27)(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid (28)(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (29)(4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid, (30)(4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-ly)methoxy)benzoyl)amino)phenyl)aceticacid, (31)(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-lymethoxy)-2,6-dimethylbenzoyl)amino)phenyl)aceticacid, and (32)(3-((4-(1,3-benzodioxol-2-lymethoxy)-2,6-dimethylbenzoylamino)-4-chlorophenyl)aceticacid, a salt thereof, a solvate thereof, or a prodrug thereof.